Ruthenium(II)-Catalyzed Migratory C-H Allylation/Hydroamination Cascade for the Synthesis of Rutaecarpine Analogues

Article abstract of DOI:10.1055/s-0037-1611525

An unprecedented allyl migration from a remote position of a quinazoline moiety through a ruthenium(II) shuttle is reported. This present cascade reaction is initiated through the formation of an η ³ -ruthenium-allyl complex followed by C-H allylation at the ortho position of the 2-aryl moiety. Finally, hydroamination with the quinazolinone -NH group, which is formed through tautomerization of the quinazoline, furnishes the annulation product. This exceedingly fast cascade reaction is complete within 10 minutes to provide rutaecarpine analogues in a single operation.

Full text of DOI:10.1055/s-0037-1611525

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
special topic
A
en
G. Bairy et al.
Special Topic
Synthesis
Ruthenium(II)-Catalyzed Migratory C–H Allylation/Hydroamination
Cascade for the Synthesis of Rutaecarpine Analogues
Gurupada Bairya,b
Arijit Nandia
Kartic Mannaa,b
Ranjan Jana*a,b
O
O
[Ru(p-cymene)Cl2]2
(5 mol%)
AgSbF6 (20 mol%)
N
N
AdCO2H (2.0 equiv)
DCE, 130 °C, 10 min
N
N
R1
R1
R2
R2
a Organic and Medicinal Chemistry Division, CSIR-Indian
Institute of Chemical Biology, 4 Raja S. C. Mullick Road,
Jadavpur, Kolkata 700032, West Bengal, India
rjana@iicb.res.in
b Academy of Scientific and Innovative Research (AcSIR),
Jadavpur, Kolkata 700032, West Bengal, India
• Remote allyl migration
25 examples
up to 90% yield
• C–H allylation/hydroamination cascade
• Quinazoline/quinazolinone tautomerization
• Exceedingly fast reaction
• Redox-neutral process
Published as part of the Special Topic Ruthenium in
Organic Synthesis
Received: 11.03.2019
Accepted after revision: 27.03.2019
Published online:
Our group is actively engaged in the synthesis of biological-
ly active heterocycles through the merger of C–H activation
and alkene difunctionalization.7 This strategy is extremely
challenging to execute since most C–H activations proceed
through a high energetic pathway at high temperature,
whereas deleterious -hydride elimination is accelerated at
this high temperature providing the Fujiwara–Moritani
Heck product as a major product.8 This inherent problem
could be circumvented through the judicious choice of the
catalyst, ligand, and reaction conditions. In this vein, we
have reported a ruthenium(II)-catalyzed divergent synthe-
sis of 2-methylindoles and indolines through a C–H allyla-
tion/cyclization cascade.7c
Recently, a few strategies have been reported for the an-
nulation of quinazolinones via C–H functionalization. For
example, the Xuan group reported a ruthenium-catalyzed
synthesis of pyrrolo[2,1-b]quinazolin-9(1H)-ones via C–H
alkenylation with activated alkenes followed by an aza-Mi-
chael addition reaction.9 Mechanistically, the formation of a
DOI: 10.1055/s-0037-1611525; Art ID: ss-2019-c0166-st
Abstract An unprecedented allyl migration from a remote position of
a quinazoline moiety through a ruthenium(II) shuttle is reported. This
present cascade reaction is initiated through the formation of an η3-ru-
thenium–allyl complex followed by C–H allylation at the ortho position
of the 2-aryl moiety. Finally, hydroamination with the quinazolinone -
NH group, which is formed through tautomerization of the quinazoline,
furnishes the annulation product. This exceedingly fast cascade reaction
is complete within 10 minutes to provide rutaecarpine analogues in a
single operation.
Key words allyl migration, C–H activation, quinazolinones, rutheni-
um(II) catalysis, cascade reaction, rutaecarpine scaffold
Quinazolines and quinazolinones represent two import-
ant classes of N-heterocycles ubiquitously found in numer-
ous natural products, agrochemicals, drugs, and pharma-
ceutically active ingredients (APIs) (Figure 1).1 While the
quinazoline scaffold is present in several blockbuster anti-
cancer drugs, including terazosin, gefitinib, erlotinib, and
lapatinib, the quinazolinones exhibit prominent antimicro-
bial properties.2 Hence, significant attention has been paid
to the synthesis and manipulation of these two scaffolds3 in
drug discovery programs. Typically, quinazolinones are eas-
ily converted into the corresponding quinazolines via chlo-
rination with thionyl chloride.4 However, the conversion of
quinazolines into the corresponding quinazolinones has
been less explored, but is in high demand to modify biolog-
ical properties.
O
N
O
N
N
N
N
HN
Rutaecarpine
Luotonin A
COX-2 inhibitor
topoisomerase I inhibitor
O
N
N
O
MeO
N
C–H activation5 is the latest technology added to the or-
ganic chemist’s toolbox which offers the ability for the rap-
id construction and late-stage modification of functional
molecules. This C–H activation is also emerging as a power-
ful tool in medicinal chemistry to accelerate hit-to-lead op-
timization through structure–activity relationship studies.6
O
N
N
HN
Me
Evodiamine
thermogenic and stimulant
(–)-Circumdatin H
mitochondrial NADH oxidase
Figure 1 Biologically active, fused quinazolinones
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
G. Bairy et al.
Special Topic
Synthesis
quinazolinone serves as an excellent leaving group.15 To ex-
amine this, we prepared 4-(allyloxy)-2-phenylquinazoline
(1a) by treatment of the corresponding quinazolinone with
allyl bromide under basic conditions.16 Interestingly, no N-
allylation product was formed and the corresponding O-al-
lylation product was isolated exclusively. Then, 1a was sub-
jected to our previously optimized reaction conditions.7d
Gratifyingly, we observed the formation of the annulation
product in excellent yield. From the NMR analysis, we ob-
served that the annulation product was similar to that of
our previously reported intermolecular process.7d Since any
deviation from the reported conditions did not improve the
yield further, we decided to proceed to study the substrate
scope of this intramolecular annulation strategy.
Our previous work
R = H
DCE
N
N
β-hydride
elimination
H
N
N
Ru(II)
OAc
NH
H
R
R = FG
TFE
X
N
ref. 7c
steric-controlled
protodemetalation
FG
N
O
O
[Ru(p-cymene)Cl2]2
(5 mol%)
AgSbF6 (20 mol%)
NH
N
AdCO2H (2.0 equiv)
DCE, 130 °C, 10 min
ref. 7d
N
+
N
R1
R1
The scope of the migratory C–H allylation/hydroamina-
tion cascade was examined with various substituted 4-(al-
lyloxy)quinazolines 1 which provided the desired dihy-
droisoquinolino[1,2-b]quinazolinones 2 under the standard
reaction conditions (Scheme 2). A wide range of functional
groups at the para position of the 2-phenyl moiety, such as
electron-donating methyl or methoxy, or electron-with-
drawing chloro, fluoro, trifluoromethyl, trifluoromethoxy,
or ester, were compatible under the reaction conditions
providing high to excellent yields (2b–h, Scheme 2). Re-
markably, a p-triflate on the 2-phenyl ring remained intact
under the standard reaction conditions, furnishing a mod-
erate yield of the desired product 2i, which indicates the
mild nature of the reaction conditions. In our previous re-
port7d (see Scheme 1), meta substitution at the 2-phenyl
ring inhibited the formation of either annulation or C–H al-
lylation product formation. Gratifyingly, in this migratory
intramolecular allylation/cyclization cascade reaction, meta
substitution at the 2-phenyl ring, such as methoxy, fluoro,
bromo, or phenoxy, gave effective substrates, providing
moderate to good yields (2j–m, Scheme 2). Furthermore, 2-
heteroaromatic 4-(allyloxy)quinazolines, such as 2-thio-
phenyl, afforded a moderate yield of the migratory cascade
R2
R2
OAc
This work
O
N
[Ru(p-cymene)Cl2]2
(5 mol%)
AgSbF6 (20 mol%)
O
N
N
AdCO2H (2.0 equiv)
DCE, 130 °C, 10 min
N
R1
R1
R2
R2
• Remote allyl migration
• C–H allylation/hydroamination cascade
• Quinazoline/quinazolinone tautomerization
• Exceedingly fast reaction
• Redox-neutral process
Scheme 1 Annulation through C–H allylation/hydroamination cascades
six-membered ring10 through metal-mediated cyclization is
more challenging than a five-membered ring due to the for-
mation of an energetically disfavorable seven-membered
cyclic intermediate and the lack of a proper trajectory.11 For
example, the Peng group obtained a mixture of six-mem-
bered and five-membered heterocycles in the rhodium-cat-
alyzed C–H alkylation/cyclization of 2-arylquinazolin-4-
ones with vinyl trifluoroacetate.12
Xia and Dong reported a ruthenium(II)-catalyzed syn-
thesis of indolo[2,1-a]isoquinolines via C–H allylation and
oxidative cyclization of 2-phenylindoles;13 but, selective
monoallylation was impossible to achieve. Cui and co-
workers reported a palladium-catalyzed synthesis of fused
polyheterocycles through sequential [4+2]- and [3+2]-cyclo-
additions with alkynes.14 Recently, we have developed a ru-
thenium(II)-catalyzed, intermolecular C–H allylation/hy-
droamination cascade for the synthesis of dihydroisoquino-
lino[1,2-b]quinazolinones (Scheme 1).7d Taking a cue from
this study, we assumed that 2-arylquinazolinones may also
provide a suitable platform to study the C–H allylation/hy-
droamination cascade in an intramolecular fashion. We re-
port herein a mechanistically distinct migratory sp2 C–H al-
lylation/hydroamination cascade under ruthenium(II) ca-
talysis to provide rutaecarpine derivatives.
product
2n.
Gratifyingly,
4-(allyloxy)-2-(2-naphth-
yl)quinazoline provided the corresponding cyclized product
2o in high yield, whereas the 1-naphthyl derivative did not
furnish any cyclized product.
To examine the substitution effect on the aryl ring of 4-
(allyloxy)quinazolines, we prepared several substrates with
different electron-donating and -withdrawing groups on
the fused arene and subjected them to the standard reac-
tion conditions. Gratifyingly, quinazolines derived from
benzaldehyde and 5-methylanthranilamide or 5-methoxy-
anthranilamide afforded the desired cascade products 2p
and 2q in good yields (Scheme 2). Quinazolines derived
from benzaldehyde and 4-methoxyanthranilamide, 4-
methylanthranilamide, or 4-bromoanthranilamide afforded
the desired cyclization products 2r–t in good to high yields.
In the case of an electron-withdrawing ester group at the
para position of the 2-phenyl ring, methyl substitution on
the quinazoline backbone also furnished the desired prod-
Our hypothesis to initiate the investigation of this intra-
molecular allyl migration is based on the facile tautomeri-
zation of the quinazoline/quinazolinone system, where
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
G. Bairy et al.
Special Topic
Synthesis
uct 2u in good yield (70%). 2-Naphthyl substitution at the
2-position and methyl substitution on the quinazoline moi-
ety also provided the desired product 2v in high yield
(Scheme 2). Similarly, 2-heteroaromatics, such as 2-(1-
methylpyrrolyl) and 2-thiophenyl, and methyl substitution
on the quinazoline backbone provided the corresponding
cyclized products 2w and 2x in moderate to good yields. In
the case of the quinazoline derived from 3-methylanthra-
nilamide and thiophene-2-carboxaldehyde, the desired mi-
gratory annulation product 2x was observed selectively via
sp2 C–H activation, and no sp3 C–H activation of the methyl
group was observed. 4-(Allyloxy)-2-(N-methyl-2-indo-
lyl)quinazoline also furnished the corresponding cyclized
product 2y (Scheme 2), albeit in low yield, but this product
from the indole derivative resembles the structure of rutae-
carpine. The compounds have been well-characterized with
representative X-ray crystallographic analysis of com-
pounds 2m (CCDC 1901506) and 2v (CCDC 1901505; see
the Supporting Information).
To gain mechanistic insight, when 4-(allyloxy)-2-
phenylquinazoline (1a) was subjected to the standard reac-
tion conditions in the absence of acid additive, the desired
annulation product 2a was obtained in 20% yield along with
the corresponding ortho C–H allylation product in 50% yield
O
N
O
[Ru(p-cymene)Cl2]2 (5 mol%)
N
AgSbF6 (20 mol%)
AdCO2H (2 equiv)
DCE, 130 °C, 10 min
N
N
R1
R1
R2
R2
N
2a–y
1a–y
O
N
O
O
N
O
O
N
N
N
N
N
N
N
2c: 64%
2b: 87%
2d: 67%
2e: 54%
2a: 90%
OMe
Cl
F
O
O
O
N
N
O
O
N
N
N
N
N
OMe
N
N
N
CF3
OCF3
CO2Me
OPh
OTf
2f: 68%
2h: 65%
2j: 62%
2g: 63%
2i: 45%
O
O
O
O
N
N
N
N
F
Br
N
N
N
N
S
2n: 49%
2k: 42%
2l: 40%
2m: 46%
CCDC 1901506
O
O
O
O
O
N
N
MeO
N
N
N
N
N
MeO
N
N
N
2o: 73%
2p: 64%
2q: 67%
2r: 67%
2s: 62%
O
N
O
N
O
N
N
N
Br
N
CO2Me
2t: 70%
2u: 70%
2v: 81%
CCDC 1901505
O
N
N
O
N
O
N
N
N
MeN
S
MeN
2w: 47%
2x: 71%
2y: 27%
Scheme 2 Substrate scope of the annulation cascade. All reactions were carried out on a 0.2 mmol scale. Yields refer to the average of isolated yields of
at least two experiments.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
G. Bairy et al.
Special Topic
Synthesis
(Scheme 3a). When deuterated D5-1a was subjected to the
reaction conditions without the ruthenium complex, no re-
action or deuterium exchange took place (Scheme 3b).
uct17 followed by ortho C–H ruthenation and annulation
may provide an isomeric 5-methylated product. However,
to our surprise, when the corresponding N-allylation prod-
uct 3a was prepared separately and subjected to the stan-
dard reaction conditions, the same annulation product 2a
was isolated, suggesting the N-deallylation pathway
(Scheme 3d). Furthermore, when the preformed 2-(o-allyl-
phenyl)quinazolinone 4a was subjected to the reaction con-
ditions, the cyclization product was obtained in 84% yield.
This experiment suggests that the reaction may proceed
through sp2 C–H allylation at the ortho position of the 2-
phenyl ring. Thus, allyl migration to the ortho position may
take place either through the formation of an η3-rutheni-
um–allyl complex directly from O-allylated substrate via C–O
bond cleavage or via a 3,3-sigmatropic rearrangement to
furnish the corresponding N-allylation product followed by
C–N bond cleavage. However, all our efforts to isolate this
N-allylated intermediate during the course of the reaction
were in vain. When the same reaction was performed in the
absence of ruthenium catalyst, no annulation product was
obtained from C–H allylation intermediate 4a suggesting
that, although a stoichiometric amount of acid additive is
essential for protodemetalation in the hydroamination step,
the ruthenium catalyst is involved in both the C–C and C–N
bond-formation cascade (Scheme 3e). To probe the proto-
demetalation step, when 1a was subjected to the reaction
conditions in the presence of 2.0 equivalents of CD3CO2D in
lieu of adamantylcarboxylic acid (AdCO2H), 57% yield of the
cyclized product was observed with 77% deuterium incor-
poration at the 6-methyl group (Scheme 3f).
O
O
a)
[Ru(p-cymene)Cl2]2 (5 mo%)
N
N
AgSbF6 (20 mol%)
DCE, 130 °C, 10 min
N
O
N
N
no acid
20% yield
b)
O
N
N
AgSbF6 (20 mol%)
AdCO2H (2 equiv)
N
DCE, 130 °C, 10 min
without metal
no H/D
exchange
D5
D5
c)
O
O
N
N
standard reaction
N
conditions
kH/kD = 1.9
N
2a/2a-D4
H4/D4
1a/1a-D5
H5/D5
O
N
O
N
N
d)
[Ru(p-cymene)Cl2]2 (5 mol%)
AgSbF6 (20 mol%)
AdCO2H (2 equiv)
DCE, 130 °C, 10 min
N
3a
R
R
2a: R = H, 90% yield
2h: R = CO2Me, 67% yield
e)
O
O
[Ru(p-cymene)Cl2]2 (5 mol%)
AgSbF6 (20 mol%)
NH
N
N
N
AdCO2H (2 equiv)
DCE, 130 °C, 10 min
Therefore, based on these control experiments and pre-
vious reports,7c,d,18 a plausible mechanism for this cascade
reaction is proposed, as depicted in Scheme 4. Both AgSbF6
and AdCO2H are prerequisite additives for the formation of
an electrophilic active ruthenium catalyst A where the
chloride ion is replaced by the noncoordinating SbF6– anion
as AgCl precipitation. On the other hand, this active ruthe-
nium species facilitates the deallylation of 4-(ally-
loxy)quinazolines, presumably via η3-ruthenium–allyl
complex formation. Then, coordination of the nitrogen
atom of substrate 1a to the η3-ruthenium–allyl complex
produces complex B, which undergoes sp2 ortho C–H inser-
tion to form five-membered ruthenacycle C either in a con-
certed manner (path a) or via a 3,3-sigmatropic rearrange-
ment to furnish the corresponding N-allylation product B′
followed by C–N bond cleavage (path b). This coordinately
unsaturated ruthenium complex undergoes allyl migration
to the ortho position of the 2-aryl moiety for C–H allylation
to generate intermediate D.7c,d,19 Again, coordination of the
ruthenium complex between the amide nitrogen atom and
alkene of intermediate D produces intermediate E. Subse-
quently, the active ruthenium complex undergoes migra-
tory alkene insertion into the allyl moiety to produce inter-
mediate F through intramolecular C–N bond formation. In-
termediate F undergoes protodemetalation in the presence
4a
84% yield
without [Ru] cat; no reaction
f)
H/D
O
O
N
N
[Ru(p-cymene)Cl2]2 (5 mol%)
AgSbF6 (20 mol%)
N
N
CD3CO2D (2 equiv)
DCE, 130 °C, 10 min
57% yield
77% D incorporation
Scheme 3 Control experiments
These experiments suggest that
a stoichiometric
amount of acid additive is needed for the cyclization prod-
uct formation and that cationic ruthenium species have a
dual role in this migratory cyclization cascade. In the pres-
ence of ruthenium catalyst and silver(I) additive, both deal-
lylation of the 4-(allyloxy)quinazoline and metal-catalyzed
migratory ortho allylation take place in a concerted manner.
From a competitive kinetic study between 1a and the corre-
sponding deuterated substrate D5-1a, the primary kinetic
isotope effect (KIE) was determined as kH/kD = 1.9, suggest-
ing that the C–H activation step may be involved in the rate-
limiting step (Scheme 3c). Mechanistically, an initial 3,3-
sigmatropic rearrangement to provide N-allylation prod-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
G. Bairy et al.
Special Topic
Synthesis
of AdCO2H to produce the desired annulation product 2a.
The active catalyst is regenerated for subsequent runs from
the ruthenium hydride species, presumably through the ex-
trusion of hydrogen gas reacting with AdCO2H.20
TMS. Standard abbreviations are used to denote peak multiplicities.
Coupling constants, J, are reported in hertz (Hz). HRMS (m/z) data
were measured using ESI techniques on a Q-Tof Micro mass spec-
trometer.
Isoquinolino[1,2-b]quinazolinones 2a–y via a Ruthenium(II)-Cata-
lyzed Migratory C–H Allylation/Hydroamination Cascade; General
Procedure
[RuCl2(L)]2
AgX + RCO2H
A mixture of the 4-(allyloxy)-2-phenylquinazoline (0.2 mmol), [Ru(p-
cymene)Cl2]2 (0.01 mmol, 5 mol%), AgSbF6 (0.04 mmol, 20 mol%), and
adamantylcarboxylic acid (AdCO2H; 0.4 mmol, 2.0 equiv) was taken
into a 15-mL pressure tube. To this reaction mixture, DCE (2.0 mL)
was added and the closed reaction mixture was allowed to stir at
130 °C for 10 min. After 10 min, the reaction mixture was cooled to
ambient temperature, then diluted with CH2Cl2, washed with 1 N
NaOH solution to neutralize the excess acid, dried over anhydrous
Na2SO4, and concentrated under reduced pressure to obtain the crude
product. Purification by silica gel column chromatography (EtO-
Ac/hexane) afforded the desired isoquinolino[1,2-b]quinazolinone
product 2a–y.
AgCl
2a
1a
[Ru(L)(κ2−OCOR)]+[X]–
RCO2H
n
protodemetalation
A
L = p-cymene
n = 1 or 2
O
Ru
O
N
L
N
[R = adamantyl]
–
X = SbF6
N
Ru
L
N
X
path b
H
F
O
B
migratory
insertion
path a
HX
N
C–H activation
O
N
Ru
L
O
N
L
X
B'
Ru
H
6-Methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (2a)
N
NH
Column chromatography (hexane/EtOAc, 19:1) afforded 2a as a color-
less solid; yield: 47.16 mg (90%); mp 110–112 °C. When the same re-
action was performed on a 1.0 mmol scale, the desired product 2a
was obtained in 71% yield.
C–H activation
N
E
HX
Ru
C
O
1H NMR (600 MHz, CDCl3):  = 8.52 (d, J = 7.2 Hz, 1 H), 8.34 (dd, J = 7.8,
1.2 Hz, 1 H), 7.80–7.75 (m, 2 H), 7.53–7.45 (m, 3 H), 7.30 (d, J = 7.2 Hz,
1 H), 5.62–5.57 (m, 1 H), 3.40 (dd, J = 15.6, 6.0 Hz, 1 H), 2.92 (dd, J =
15.6, 1.2 Hz, 1 H), 1.26 (d, J = 7.2 Hz, 3 H).
NH
[Ru(L)(κ2−OCOR)]+ [X]–
allyl migration
n
N
D
13C NMR (150 MHz, CDCl3):  = 161.3, 148.6, 147.7, 134.8, 134.2,
131.9, 128.9, 128.6, 127.9, 127.54, 127.48, 126.8, 126.5, 120.8, 45.4,
33.5, 18.0.
Scheme 4 Plausible mechanism
HRMS (ESI): m/z [M + H]+ calcd for C17H15N2O: 263.1184; found:
263.1181.
In conclusion, we have disclosed a ruthenium(II)-cata-
lyzed novel C–H allylation/hydroamination cascade for the
annulation of 2-arylquinazolinones. Tautomerization of the
quinazoline/quinazolinone moiety offers a suitable plat-
form for the remote allyl migration in a concerted manner.
Interestingly, besides C–O bond activation of the allyl moi-
ety, similar products are also obtained from the corre-
sponding N-allylquinazolinones through C–N bond activa-
tion. A series of rutaecarpine derivatives were synthesized
in high yields.
3,6-Dimethyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (2b)
Column chromatography (hexane/EtOAc, 19:1) afforded 2b as a white
solid; yield: 48.02 mg (87%); mp 116–118 °C.
1H NMR (600 MHz, CDCl3):  = 8.37 (d, J = 8.4 Hz, 1 H), 8.31 (d, J = 7.8
Hz, 1 H), 7.75–7.74 (m, 2 H), 7.47–7.43 (m, 1 H), 7.24 (d, J = 7.8 Hz, 1
H), 7.08 (s, 1 H), 5.58–5.54 (m, 1 H), 3.34 (dd, J = 15.6, 6.0 Hz, 1 H),
2.84 (dd, J = 16.2, 1.8 Hz, 1 H), 2.43 (s, 3 H), 1.23 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 161.4, 148.7, 147.9, 142.5, 134.8,
134.1, 129.2, 128.4, 127.9, 127.4, 126.8, 126.3, 126.2, 120.7, 45.4, 33.5,
21.6, 18.0.
All manipulations with air-sensitive reagents were carried out under
a dry nitrogen atmosphere. Unless otherwise stated, all commercial
reagents were used without additional purification. Solvents were
dried using standard methods and distilled before use. The starting 4-
(allyloxy)-2-phenylquinazoline (1a) and substituted 4-(allyloxy)-2-
phenylquinazolines 1b–y were prepared using literature methods.21,22
TLC was performed on silica gel plates (Merck silica gel 60, F254), and
the spots were visualized with UV light (254 and 365 nm) or by char-
ring the plate dipped in KMnO4. 1H NMR spectra were recorded at 300
MHz, 400 MHz, or 600 MHz frequency and 13C NMR spectra were re-
corded at 75 MHz, 100 MHz, or 150 MHz frequency on Bruker DPX,
JEOL JNM-ECZ400S/L1, and Bruker Avance instruments, respectively,
in CDCl3 solvent using TMS as the internal standard. Chemical shifts
were measured in parts per million (ppm) referenced to 0.0 ppm for
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O: 277.1341; found:
277.1277.
3-Methoxy-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-
one (2c)
Column chromatography (hexane/EtOAc, 9:1) afforded 2c as a white
solid; yield: 37.38 mg (64%); mp 158–160 °C.
1H NMR (600 MHz, CDCl3):  = 8.44 (d, J = 8.4 Hz, 1 H), 8.30 (d, J = 7.8
Hz, 1 H), 7.74 (dd, J = 4.8, 1.2 Hz, 2 H), 7.45–7.42 (m, 1 H), 6.97 (dd, J =
8.4, 2.4 Hz, 1 H), 6.78 (d, J = 3.0 Hz, 1 H), 5.59–5.55 (m, 1 H), 3.91 (s, 3
H), 3.36 (dd, J = 15.6, 6.0 Hz, 1 H), 2.85 (dd, J = 16.2, 1.8 Hz, 1 H), 1.26
(d, J = 7.2 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

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13C NMR (150 MHz, CDCl3):  = 162.6, 161.4, 148.6, 148.0, 136.9,
134.1, 130.0, 127.2, 126.8, 126.0, 121.6, 120.5, 113.5, 113.4, 55.4, 45.3,
33.8, 17.9.
13C NMR (150 MHz, CDCl3):  = 161.1, 151.7, 147.6, 147.3, 137.1,
134.3, 130.0, 127.6, 127.5, 126.9, 126.7, 125.5, 120.8, 120.2, 119.6,
45.2, 33.5, 18.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O2: 293.1290; found:
HRMS (ESI): m/z [M + H]+ calcd for C18H14F3N2O2: 347.1007; found:
293.1291.
347.1010.
3-Chloro-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one
(2d)
Methyl 6-Methyl-8-oxo-6,8-dihydro-5H-isoquinolino[1,2-
b]quinazoline-3-carboxylate (2h)
Column chromatography (hexane/EtOAc, 19:1) afforded 2d as a white
Column chromatography (hexane/EtOAc, 9:1) afforded 2h as a white
solid; yield: 39.66 mg (67%); mp 160–162 °C.
solid; yield: 41.60 mg (65%); mp 200–202 °C.
1H NMR (400 MHz, CDCl3):  = 8.44 (d, J = 8.4 Hz, 1 H), 8.29 (dt, J = 7.6,
1.2 Hz, 1 H), 7.75–7.73 (m, 2 H), 7.47–7.43 (m, 1 H), 7.41–7.38 (m, 1
H), 7.28 (t, J = 1.2 Hz, 1 H), 5.59–5.52 (m, 1 H), 3.34 (dd, J = 16.0, 6.0
Hz, 1 H), 2.86 (dd, J = 16.0, 1.6 Hz, 1 H), 1.23 (d, J = 6.8 Hz, 3 H).
1H NMR (600 MHz, CDCl3):  = 8.59 (d, J = 7.8 Hz, 1 H), 8.34 (d, J = 7.8
Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.99 (s, 1 H), 7.81–7.78 (m, 2 H),
7.52–7.50 (m, 1 H), 5.63–5.59 (m, 1 H), 3.98 (s, 3 H), 3.38 (dd, J = 15.6,
6.0 Hz, 1 H), 3.01 (dd, J = 15.6, 1.8 Hz, 1 H), 1.23 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 161.2, 147.8, 147.6, 138.2, 136.6,
134.4, 129.6, 128.7, 128.0, 127.62, 127.58, 127.0, 126.8, 120.9, 45.4,
33.5, 18.1.
13C NMR (150 MHz, CDCl3):  = 166.4, 161.1, 147.6, 147.5, 134.9,
134.4, 133.0, 132.8, 129.9, 128.5, 128.0, 127.7, 127.0, 126.9, 121.0,
52.5, 45.3, 33.5, 18.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H14ClN2O: 297.0795; found:
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2O3: 321.1239; found:
297.0797.
321.1237.
3-Fluoro-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one
6-Methyl-8-oxo-6,8-dihydro-5H-isoquinolino[1,2-b]quinazolin-3-
(2e)
yl Trifluoromethanesulfonate (2i)
Column chromatography (hexane/EtOAc, 19:1) afforded 2e as a white
Column chromatography (hexane/EtOAc, 19:1) afforded 2i as a gray
solid; yield: 30.24 mg (54%); mp 120–122 °C.
solid; yield: 36.90 mg (45%); mp 110–112 °C.
1H NMR (400 MHz, CDCl3):  = 8.52–8.48 (m, 1 H), 8.29 (dt, J = 8.0, 1.2
Hz, 1 H), 7.74–7.72 (m, 2 H), 7.46–7.42 (m, 1 H), 7.13–7.08 (m, 1 H),
6.98–6.96 (m, 1 H), 5.59–5.52 (m, 1 H), 3.35 (dd, J = 16.0, 6.0 Hz, 1 H),
2.86 (dd, J = 16.0, 1.6 Hz, 1 H), 1.23 (d, J = 6.8 Hz, 3 H).
1H NMR (300 MHz, CDCl3):  = 8.62 (d, J = 8.7 Hz, 1 H), 8.35 (d, J = 7.8
Hz, 1 H), 7.81–7.75 (m, 2 H), 7.53–7.47 (m, 1 H), 7.34 (dd, J = 8.7, 2.4
Hz, 1 H), 7.25 (d, J = 6.3 Hz, 1 H), 5.65–5.58 (m, 1 H), 3.42 (dd, J = 16.2,
6.0 Hz, 1 H), 2.96 (dd, J = 16.2, 1.8 Hz, 1 H), 1.26 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 165.1 (d, J = 252.3 Hz), 161.2, 147.9 (d,
J = 0.8 Hz), 147.7, 137.7 (d, J = 8.9 Hz), 134.4, 130.8 (d, J = 9.2 Hz),
127.5, 127.0, 126.6, 125.3 (d, J = 3.1 Hz), 120.8, 115.5 (d, J = 22.0 Hz),
115.1 (d, J = 21.9 Hz), 45.4, 33.7 (d, J = 1.4 Hz), 18.1.
13C NMR (75 MHz, CDCl3):  = 161.0, 151.5, 150.8, 147.4, 146.9, 137.6,
134.4, 130.4, 129.3, 127.7, 127.0, 126.9, 121.3, 120.9, 120.5, 45.2, 33.5,
18.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H14F3N2O4S: 411.0626; found:
411.0624.
HRMS (ESI): m/z [M + H]+ calcd for C17H14FN2O: 281.1090; found:
281.1093.
4-Methoxy-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-
6-Methyl-3-(trifluoromethyl)-5H-isoquinolino[1,2-b]quinazolin-
8(6H)-one (2f)
one (2j)
Column chromatography (hexane/EtOAc, 9:1) afforded 2j as a yellow-
Column chromatography (hexane/EtOAc, 9:1) afforded 2f as a white
ish white solid; yield: 36.21 mg (62%); mp 128–130 °C.
solid; yield: 44.88 mg (68%); mp 98–100 °C.
1H NMR (400 MHz, CDCl3):  = 8.30 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0
Hz, 1 H), 7.76–7.70 (m, 2 H), 7.45–7.41 (m, 1 H), 7.36 (t, J = 8.0 Hz, 1
H), 7.02 (d, J = 8.0 Hz, 1 H), 5.59–5.53 (m, 1 H), 3.87 (s, 3 H), 3.29 (d, J =
16.4 Hz, 1 H), 2.93 (dd, J = 16.8, 6.0 Hz, 1 H), 1.21 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 161.4, 156.9, 148.7, 147.9, 134.2,
130.2, 127.8, 127.6, 126.9, 126.5, 123.9, 121.0, 119.8, 113.1, 55.8, 45.1,
26.5, 18.4.
1H NMR (600 MHz, CDCl3):  = 8.65 (d, J = 8.4 Hz, 1 H), 8.34 (dd, J = 7.8,
1.2 Hz, 1 H), 7.81–7.77 (m, 2 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.57 (s, 1 H),
7.52–7.50 (m, 1 H), 5.64–5.59 (m, 1 H), 3.43 (dd, J = 16.2, 6.0 Hz, 1 H),
3.00 (dd, J = 16.2, 1.2 Hz, 1 H), 1.26 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 161.1, 147.4, 147.2, 135.5, 134.4,
133.3 (q, J = 21.6 Hz), 132.2, 127.7, 127.1, 127.0 (q, J = 273.2 Hz),
126.9, 125.5 (q, J = 2.1 Hz), 124.6, 124.3 (q, J = 2.4 Hz), 121.0, 45.2,
33.5, 18.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O2: 293.1290; found:
293.1289.
HRMS (ESI): m/z [M + H]+ calcd for C18H14F3N2O: 331.1058; found:
331.1053.
4-Fluoro-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one
(2k)
6-Methyl-3-(trifluoromethoxy)-5H-isoquinolino[1,2-
b]quinazolin-8(6H)-one (2g)
Column chromatography (hexane/EtOAc, 19:1) afforded 2k as a yel-
lowish white solid; yield: 23.52 mg (42%); mp 136–138 °C.
Column chromatography (hexane/EtOAc, 9:1) afforded 2g as a gray
solid; yield: 43.60 mg (63%); mp 84–86 °C.
1H NMR (400 MHz, CDCl3):  = 8.52 (d, J = 8.4 Hz, 1 H), 8.28 (dt, J = 8.0,
1.2 Hz, 1 H), 7.73–7.72 (m, 2 H), 7.46–7.42 (m, 1 H), 7.25–7.22 (m, 1
H), 7.10 (s, 1 H), 5.59–5.52 (m, 1 H), 3.36 (dd, J = 16.0, 5.6 Hz, 1 H),
2.88 (dd, J = 16.4, 1.6 Hz, 1 H), 1.23 (d, J = 6.8 Hz, 3 H).
1H NMR (600 MHz, CDCl3):  = 8.34–8.31 (m, 2 H), 7.77 (d, J = 4.2 Hz, 2
H), 7.51–7.47 (m, 1 H), 7.43–7.40 (m, 1 H), 7.28–7.25 (m, 1 H), 5.66–
5.61 (m, 1 H), 3.26 (d, J = 16.8 Hz, 1 H), 3.10 (dd, J = 16.2, 6.0 Hz, 1 H),
1.26 (d, J = 7.2 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

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13C NMR (150 MHz, CDCl3):  = 161.1, 160.2 (d, J = 243.9 Hz), 147.51,
147.48, 134.3, 131.1 (d, J = 5.0 Hz), 128.3 (d, J = 8.1 Hz), 127.6, 126.8
(d, J = 11.6 Hz), 123.48, 123.45, 122.1 (d, J = 19.6 Hz), 120.9, 118.2 (d,
J = 21.5 Hz), 44.8, 26.0 (d, J = 3.2 Hz), 18.3.
HRMS (ESI): m/z [M + H]+ calcd for C17H14FN2O: 281.1090; found:
281.1087.
1H NMR (600 MHz, CDCl3):  = 9.06 (s, 1 H), 8.36 (dd, J = 8.4, 1.8 Hz, 1
H), 8.05 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 2 H), 7.81–7.78 (m, 1 H),
7.74 (s, 1 H), 7.60–7.57 (m, 1 H), 7.55–7.52 (m, 1 H), 7.51–7.48 (m, 1
H), 5.69–5.64 (m, 1 H), 3.51 (dd, J = 15.6, 5.4 Hz, 1 H), 3.11 (dd, J =
15.6, 1.8 Hz, 1 H), 1.25 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 161.4, 149.0, 147.9, 135.0 (2C), 134.3,
132.5, 131.1, 129.4, 128.9, 128.1, 127.5, 127.1 (2C), 126.9, 126.5,
126.2, 120.8, 45.7, 34.1, 18.1.
4-Bromo-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one
(2l)
HRMS (ESI): m/z [M + H]+ calcd for C21H17N2O: 313.1341; found:
313.1333.
Column chromatography (hexane/EtOAc, 19:1) afforded 2l as a white
solid; yield: 27.20 mg (40%); mp 158–160 °C.
1H NMR (400 MHz, CDCl3):  = 8.63 (d, J = 2.0 Hz, 1 H), 8.29 (dt, J = 7.6,
1.2 Hz, 1 H), 7.76 (d, J = 0.8 Hz, 1 H), 7.75–7.74 (m, 1 H), 7.59 (dd, J =
8.0, 2.0 Hz, 1 H), 7.48–7.44 (m, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 5.58–5.51
(m, 1 H), 3.28 (dd, J = 16.0, 6.0 Hz, 1 H), 2.86 (dd, J = 16.0, 1.6 Hz, 1 H),
1.22 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 161.2, 147.6, 147.2, 134.8, 134.5,
133.7, 131.0, 130.8, 130.4, 127.7, 127.0, 126.9, 121.4, 121.1, 45.4, 33.2,
18.2.
6,10-Dimethyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (2p)
Column chromatography (hexane/EtOAc, 19:1) afforded 2p as a yel-
lowish gummy liquid; yield: 35.33 mg (64%).
1H NMR (400 MHz, CDCl3):  = 8.45 (dd, J = 7.6, 1.2 Hz, 1 H), 8.08 (d, J =
1.2 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.56–7.53 (m, 1 H), 7.45 (td, J =
7.2, 1.2 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.25 (d, J = 7.2 Hz, 1 H), 5.58–5.52
(m, 1 H), 3.35 (dd, J = 16.0, 6.0 Hz, 1 H), 2.87 (dd, J = 16.0, 1.6 Hz, 1 H),
2.48 (s, 3 H), 1.21 (d, J = 6.8 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H14BrN2O: 341.0290; found:
341.0293.
13C NMR (100 MHz, CDCl3):  = 161.3, 147.9, 145.8, 136.8, 135.8,
134.8, 131.8, 129.2, 128.7, 127.8, 127.6, 127.4, 126.3, 120.7, 45.4, 33.7,
21.5, 18.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O: 277.1341; found:
6-Methyl-4-phenoxy-5H-isoquinolino[1,2-b]quinazolin-8(6H)-
one (2m)
277.1342.
Column chromatography (hexane/EtOAc, 19:1) afforded 2m as a yel-
lowish white solid; yield: 32.57 mg (46%); mp 124–126 °C.
10-Methoxy-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-
1H NMR (400 MHz, CDCl3):  = 8.34–8.29 (m, 2 H), 7.78 (dd, J = 8.4, 1.2
Hz, 1 H), 7.75 (td, J = 8.4, 1.6 Hz, 1 H), 7.48–7.44 (m, 1 H), 7.39 (td, J =
8.0, 1.2 Hz, 1 H), 7.34–7.30 (m, 2 H), 7.13 (dd, J = 8.0, 1.2 Hz, 1 H),
7.10–7.06 (m, 1 H), 6.94–6.91 (m, 2 H), 5.58–5.51 (m, 1 H), 3.24 (dd, J
= 16.8, 1.6 Hz, 1 H), 2.99 (dd, J = 16.4, 6.0 Hz, 1 H), 1.23 (d, J = 6.8 Hz, 3
H).
13C NMR (100 MHz, CDCl3):  = 161.3, 157.6, 154.1, 148.3, 147.7,
134.4, 131.1, 129.9, 128.3, 127.7, 127.2, 127.0, 126.8, 123.7, 123.2,
123.0, 121.0, 117.6, 45.1, 27.2, 18.3.
one (2q)
Column chromatography (hexane/EtOAc, 19:1) afforded 2q as a white
solid; yield: 39.13 mg (67%); mp 126–128 °C.
1H NMR (400 MHz, CDCl3):  = 8.44 (dd, J = 7.6, 1.2 Hz, 1 H), 7.70 (d, J =
8.8 Hz, 1 H), 7.66 (d, J = 3.2 Hz, 1 H), 7.45 (td, J = 7.2, 1.6 Hz, 1 H), 7.42–
7.38 (m, 1 H), 7.34 (dd, J = 8.8, 2.8 Hz, 1 H), 7.24 (d, J = 6.4 Hz, 1 H),
5.60–5.53 (m, 1 H), 3.92 (s, 3 H), 3.35 (dd, J = 16.0, 5.6 Hz, 1 H), 2.87
(dd, J = 16.0, 1.6 Hz, 1 H), 1.22 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 161.1, 158.4, 146.7, 142.5, 134.6,
131.6, 129.22, 129.16, 128.7, 127.7, 127.6, 124.8, 121.7, 106.2, 55.9,
45.6, 33.7, 18.1.
HRMS (ESI): m/z [M + K]+ calcd for C23H18N2O2K: 393.1005; found:
393.1011.
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O2: 293.1290; found:
293.1295.
5-Methyl-4H-thieno[2′,3′:3,4]pyrido[2,1-b]quinazolin-7(5H)-one
(2n)
Column chromatography (hexane/EtOAc, 19:1) afforded 2n as a yel-
11-Methoxy-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-
lowish white solid; yield: 26.26 mg (49%); mp 116–118 °C.
one (2r)
1H NMR (300 MHz, CDCl3):  = 8.28 (d, J = 7.8 Hz, 1 H), 7.75–7.66 (m, 2
H), 7.55 (d, J = 5.1 Hz, 1 H), 7.44–7.38 (m, 1 H), 6.99 (d, J = 5.1 Hz, 1 H),
5.66–5.58 (m, 1 H), 3.25 (dd, J = 16.8, 6.6 Hz, 1 H), 2.97 (d, J = 16.5 Hz,
1 H), 1.32 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 161.0, 147.8, 145.8, 140.4, 134.2, 131.7,
130.6, 127.8, 127.0, 126.95, 126.1, 121.0, 46.8, 29.9, 18.7.
Column chromatography (hexane/EtOAc, 19:1) afforded 2r as a white
solid; yield: 39.13 mg (67%); mp 80–82 °C.
1H NMR (400 MHz, CDCl3):  = 8.46 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 8.8
Hz, 1 H), 7.48 (td, J = 8.8, 1.2 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.26 (d,
J = 7.2 Hz, 1 H), 7.15 (d, J = 1.6 Hz, 1 H), 7.02 (dd, J = 8.8, 2.4 Hz, 1 H),
5.57–5.51 (m, 1 H), 3.93 (s, 3 H), 3.35 (dd, J = 15.6, 5.6 Hz, 1 H), 2.87
(dd, J = 16.4, 1.6 Hz, 1 H), 1.21 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.6, 160.9, 149.4, 135.1, 132.0,
131.0, 128.7, 128.5, 127.9, 127.6, 117.0, 114.6, 107.9, 100.0, 55.8, 45.2,
33.7, 18.1.
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2OS: 269.0749; found:
269.0743.
7-Methyl-7,8-dihydro-5H-benzo[6,7]isoquinolino[1,2-
b]quinazolin-5-one (2o)
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O2: 293.1290; found:
293.1292.
Column chromatography (hexane/EtOAc, 19:1) afforded 2o as a yel-
lowish white solid; yield: 45.55 mg (73%); mp 218–220 °C.
6,11-Dimethyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (2s)
Column chromatography (hexane/EtOAc, 19:1) afforded 2s as a gray
solid; yield: 34.22 mg (62%); mp 106–108 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

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Synthesis
1H NMR (300 MHz, CDCl3):  = 8.47 (dd, J = 7.5, 1.8 Hz, 1 H), 8.20 (d, J =
8.1 Hz, 1 H), 7.57 (s, 1 H), 7.52–7.40 (m, 2 H), 7.28 (d, J = 8.1 Hz, 2 H),
5.59–5.53 (m, 1 H), 3.37 (dd, J = 16.2, 6.0 Hz, 1 H), 2.89 (dd, J = 15.9,
1.5 Hz, 1 H), 2.52 (s, 3 H), 1.22 (d, J = 6.9 Hz, 3 H).
1,5,9-Trimethyl-4,5-dihydropyrrolo[2′,3′:3,4]pyrido[2,1-
b]quinazolin-7(1H)-one (2w)
Column chromatography (hexane/EtOAc, 19:1) afforded 2w as a gray
gummy liquid; yield: 26.23 mg (47%).
13C NMR (75 MHz, CDCl3):  = 161.2, 148.6, 147.9, 145.1, 134.8, 131.8,
129.1, 128.6, 128.1, 127.8, 127.5, 127.2, 126.6, 118.5, 45.2, 33.6, 21.9,
18.0.
1H NMR (600 MHz, CDCl3):  = 8.04 (s, 1 H), 7.50–7.49 (m, 2 H), 6.78
(d, J = 2.4 Hz, 1 H), 6.02 (d, J = 2.4 Hz, 1 H), 5.59–5.55 (m, 1 H), 4.15 (s,
3 H), 3.15 (dd, J = 16.2, 6.0 Hz, 1 H), 2.73 (d, J = 15.6 Hz, 1 H), 2.48 (s, 3
H), 1.30 (d, J = 6.6 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2O: 277.1341; found:
13C NMR (150 MHz, CDCl3):  = 161.5, 145.7, 143.7, 135.4, 135.2,
129.5, 126.5, 126.3, 124.5, 120.9, 120.0, 106.5, 47.1, 37.4, 27.6, 21.3,
18.4.
277.1334.
11-Bromo-6-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one
(2t)
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3O: 280.1450; found:
Column chromatography (hexane/EtOAc, 19:1) afforded 2t as a white
280.0089.
solid; yield: 47.60 mg (70%); mp 148–150 °C.
1H NMR (600 MHz, CDCl3):  = 8.45 (d, J = 7.8 Hz, 1 H), 8.43 (d, J = 1.8
Hz, 1 H), 7.83–7.81 (m, 1 H), 7.63 (d, J = 9.0 Hz, 1 H), 7.50 (t, J = 7.2 Hz,
1 H), 7.43 (t, J = 7.2 Hz, 1 H), 7.28 (d, J = 7.2 Hz, 1 H), 5.58–5.53 (m, 1
H), 3.37 (dd, J = 16.2, 6.0 Hz, 1 H), 2.90 (d, J = 16.2 Hz, 1 H), 1.23 (d, J =
7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 160.2, 148.9, 146.6, 137.4, 134.8,
132.1, 129.4, 129.3, 128.68, 128.67, 127.9, 127.6, 122.2, 119.9, 45.6,
33.4, 17.9.
5,11-Dimethyl-4H-thieno[2′,3′:3,4]pyrido[2,1-b]quinazolin-7(5H)-
one (2x)
Column chromatography (hexane/EtOAc, 19:1) afforded 2x as a white
solid; yield: 40.04 mg (71%); mp 150–152 °C.
1H NMR (600 MHz, CDCl3):  = 8.13 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 7.2
Hz, 1 H), 7.53 (d, J = 5.4 Hz, 1 H), 7.30 (t, J = 7.8 Hz, 1 H), 6.98 (d, J = 5.4
Hz, 1 H), 5.63–5.58 (m, 1 H), 3.24 (dd, J = 16.8, 6.6 Hz, 1 H), 2.96 (d, J =
16.8 Hz, 1 H), 2.64 (s, 3 H), 1.32 (d, J = 6.6 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H14BrN2O: 341.0290; found:
341.0291.
13C NMR (150 MHz, CDCl3):  = 161.3, 146.3, 144.5, 140.1, 135.5,
134.7, 131.4, 131.2, 127.7, 125.7, 124.6, 120.9, 46.7, 29.9, 18.7, 17.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2OS: 283.0905; found:
283.1031.
Methyl 6,10-Dimethyl-8-oxo-6,8-dihydro-5H-isoquinolino[1,2-
b]quinazoline-3-carboxylate (2u)
Column chromatography (hexane/EtOAc, 9:1) afforded 2u as a white
solid; yield: 46.76 mg (70%); mp 158–160 °C.
7,13-Dimethyl-7,8-dihydroindolo[2′,3′:3,4]pyrido[2,1-
b]quinazolin-5(13H)-one (2y)
1H NMR (400 MHz, CDCl3):  = 8.50 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 8.4
Hz, 1 H), 8.02 (dd, J = 8.4, 0.8 Hz, 1 H), 7.92 (s, 1 H), 7.53 (s, 1 H), 7.26
(dd, J = 8.4, 1.6 Hz, 1 H), 5.58–5.51 (m, 1 H), 3.93 (s, 3 H), 3.36 (dd, J =
16.0, 6.0 Hz, 1 H), 2.93 (d, J = 16.0 Hz, 1 H), 2.48 (s, 3 H), 1.19 (d, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 166.5, 161.0, 147.70, 147.68, 145.3,
135.0, 133.2, 132.8, 129.9, 128.7, 128.5, 128.0, 127.5, 126.8, 118.7,
52.5, 45.3, 33.6, 22.0, 18.2.
Column chromatography (hexane/EtOAc, 9:1) afforded 2y as a yellow
solid; yield: 17.01 mg (27%); mp 194–196 °C.
1H NMR (600 MHz, CDCl3):  = 8.33 (dd, J = 7.8, 1.8 Hz, 1 H), 7.76–7.70
(m, 2 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.46–7.43 (m, 2 H), 7.42–7.39 (m, 1
H), 7.22–7.19 (m, 1 H), 5.77–5.72 (m, 1 H), 4.38 (s, 3 H), 3.36 (dd, J =
16.8, 6.6 Hz, 1 H), 3.21 (dd, J = 16.2, 0.6 Hz, 1 H), 1.38 (d, J = 7.2 Hz, 3
H).
13C NMR (150 MHz, CDCl3):  = 161.3, 147.3, 144.6, 140.7, 134.1,
127.1, 127.0, 126.22, 126.16, 125.02, 124.98, 120.9, 120.1, 119.9,
116.4, 110.3, 46.8, 32.5, 25.7, 18.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H19N2O3: 335.1396; found:
335.1394.
HRMS (ESI): m/z [M + H]+ calcd for C20H18N3O: 316.1450; found:
316.1446.
3,7-Dimethyl-7,8-dihydro-5H-benzo[6,7]isoquinolino[1,2-
b]quinazolin-5-one (2v)
Column chromatography (hexane/EtOAc, 19:1) afforded 2v as a yel-
low solid; yield: 52.81 mg (81%); mp 214–216 °C.
Funding Information
1H NMR (600 MHz, CDCl3):  = 9.02 (s, 1 H), 8.13 (s, 1 H), 8.03 (d, J =
8.4 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.73 (s, 1
H), 7.60 (dd, J = 8.4, 2.4 Hz, 1 H), 7.58–7.55 (m, 1 H), 7.53–7.50 (m, 1
H), 5.67–5.63 (m, 1 H), 3.50 (dd, J = 15.6, 5.4 Hz, 1 H), 3.09 (dd, J =
15.6, 1.8 Hz, 1 H), 2.52 (s, 3 H), 1.23 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 161.3, 148.2, 145.9, 136.7, 135.8,
134.9, 132.5, 131.1, 129.3, 128.6, 127.9, 127.3, 127.2, 127.1, 127.0,
126.3, 126.2, 120.5, 45.7, 34.1, 21.4, 18.2.
This work was financially supported by the Department of Science
and Technology (DST), Science and Engineering Research Board
(SERB), Government of India (Ramanujan Fellowship Award No.
SR/S2/RJN-97/2012,
Extra
Mural
Research
Grant
No.
EMR/2014/000469). G.B. thanks UGC and K.M. thanks CSIR for their
fellowships.
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HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O: 327.1497; found:
327.1646.
Acknowledgment
We acknowledge S. Jana for X-ray crystal structure analysis.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

I
G. Bairy et al.
Special Topic
Synthesis
Supporting Information
(6) (a) Duncton, M. A. J. MedChemComm 2011, 2, 1135. (b) Caro-
Diaz, E. J. E.; Urbano, M.; Buzard, D. J.; Jones, R. M. Bioorg. Med.
Chem. Lett. 2016, 26, 5378.
(7) (a) Manna, M. K.; Hossian, A.; Jana, R. Org. Lett. 2015, 17, 672.
(b) Manna, M. K.; Bhunia, S. K.; Jana, R. Chem. Commun. 2017,
53, 6906. (c) Manna, M. K.; Bairy, G.; Jana, R. J. Org. Chem. 2018,
83, 8390. (d) Bairy, G.; Das, S.; Begam, H. M.; Jana, R. Org. Lett.
2018, 20, 7107.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611525.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I