Ruthenium-Catalyzed Regioselective C(sp2)-H Activation/Annulation of N-(7-Azaindole)amides with 1,3-Diynes Using N-Amino-7-azaindole as the N, N-Bidentate Directing Group

Article abstract of DOI:10.1021/acs.joc.1c00759

The ruthenium(II)-catalyzed regioselective annulation of N-(7-azaindole)amides with 1,3-diynes has been demonstrated. Bioactive N-amino-7-azaindole has been used as a new bidentate directing group to furnish an array of 3-alkynylated isoquinolones. Furthermore, the developed protocol works efficiently for both aryl- and heteroaryl-substituted amides producing a range of pharmacologically useful 7-azaindole-based isoquinolones with a wide range of functionality.

Full text of DOI:10.1021/acs.joc.1c00759

pubs.acs.org/joc
Article
Ruthenium-Catalyzed Regioselective C(sp2)−H Activation/
Annulation of N‑(7-Azaindole)amides with 1,3-Diynes Using
N‑Amino-7-azaindole as the N,N‑Bidentate Directing Group
Bedadyuti Vedvyas Pati,§ Prateep Singh Sagara,§ Asit Ghosh, Gopal Krushna Das Adhikari,
and Ponneri Chandrababu Ravikumar*
Cite This: J. Org. Chem. 2021, 86, 9428−9443
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The ruthenium(II)-catalyzed regioselective annula-
tion of N-(7-azaindole)amides with 1,3-diynes has been demon-
strated. Bioactive N-amino-7-azaindole has been used as a new
bidentate directing group to furnish an array of 3-alkynylated
isoquinolones. Furthermore, the developed protocol works
efficiently for both aryl- and heteroaryl-substituted amides
producing a range of pharmacologically useful 7-azaindole-based
isoquinolones with a wide range of functionality.
remains largely underdeveloped owing to their challenges
associated with chemo- and regioselectivity.7 Furthermore,
control of mono-/diannulation is an added issue in these
transformations.7a,i Hence, in order to address the above
challenges, designing a new N,N-bidentate directing group
and the selection of appropriate metal catalyst are of utmost
importance.8 In this context, Glorious and co-workers
demonstrated a rhodium-catalyzed highly selective C−H
activation/annulation of amides with 1,3-diynes (Scheme
1a-(i)).7b Also, in another report, Nicholls and co-workers
reported a regioselective C(sp2)−H activation of benzamides
with 1,3-diynes using 8-aminoquinoline as the N,N-bidentate
directing group (Scheme 1a-(ii)).7c,9 Despite these reports, to
the best of our knowledge ruthenium-catalyzed regioselective
C−H/N−H activation of amides with 1,3-diynes is elusive.
Moreover, application of N-amino-7-azaindole as a directing
group for regioselective annulation is rare. In pursuit of our
continuous effort to develop a new N,N-bidentate directing
group, herein we have demonstrated the use of N-amino-7-
azaindole for ruthenium-catalyzed regioselective C(sp2)−H
activation/annulation of amides with 1,3-diynes (Scheme 1b).
INTRODUCTION
■
Multifunctionalized isoquinolones and 7-azaindole belong to
a distinct class of N-containing heterocycles that are
widespread in numerous natural products, pharmaceuticals,
and bioactive molecules.1 Especially, various potent molecules
such as JNK inhibitors,1a anticardiac arrhythmias,1b Gp 120/
CD4 inhibitor1c BMS378806 and P13K/m 120/TOR
inhibitor1d contain the structural framework of isoquinolones
and 7-azaindole (Figure 1). Consequently, designing a facile
synthesis protocol to afford those molecules received
enormous attention over the years.
Figure 1. Representative examples of natural products and drug
molecules bearing 3-substituted isoquinoline scaffold.
RESULTS AND DISCUSSION
■
Transition metal catalyzed C−H activation has gained
phenomenal advancement over the past two decades because
of its multifaceted applications in organic syntheses.2
Particularly, rapid strides have been made in the recent
years for selective C−H bond activation of benzamides3 to
access the isoquinolone derivatives.4 In general, internal
alkynes have been widely explored as the coupling partner in
these reactions that furnished their corresponding isoquino-
lones.5,6 Nevertheless, the investigation of the conjugated
alkynes (1,3-diynes) for those analogous annulation reactions
We initiated our investigations to find the optimal reaction
conditions for the ruthenium-catalyzed oxidative C−H/C−N
Received: March 31, 2021
Published: June 25, 2021
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443
© 2021 American Chemical Society
9428

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 1. Previous and Present Work7b,c
(0.20 M) at 120 °C for the synthesis of 3aa (Table 1, entry
15).
To showcase the versatility of this developed protocol, an
array of aryl- and heteroaryl-substituted amides 1 and aryl-
and alkyl-substituted 1,3-diynes 2 were subjected to the
optimized reaction conditions (Table 2). To our delight,
amides bearing electron-donating aryl substituents worked
efficiently to give 63−82% yield of their respective annulated
adducts, 3aa−3ha. It is noteworthy that the developed
protocol was found to be compatible with heteroaromatic
thieno-substrate, producing 3ia in 61% yield. Similarly, the
reaction was also viable with the benzamides bearing
electron-withdrawing substituents on the phenyl ring (halo,
nitro, cyano, and trifluoromethyl) affording corresponding
annulated compounds 3ja−3pa. Interestingly, all the halo-
substituted arylamides produced 74−81% yield of their
respective annulated adducts, 3ja−3ma. The benzamides
bearing nitro- and cyano-substitution on the phenyl ring
resulted good yields of their respective annulated adducts.
Moreover, strongly electron-withdrawing trifluoromethyl-
substituted benzamides also furnished 3pa in good yields.
After an extensive study of the scope of the titled
transformation with para-substituted benzamides, we moved
on to explore the scope with various unsymmetrically meta-
substituted benzamides. Gratifyingly, the different meta-
substituted benzamides (such as m-methyl, m-chloro, m-
fluoro, m-nitro, and m-trifluoromethyl) reacted smoothly to
furnish desired annulated products 3qa−3ua respectively in
68−81% yield. It is worth mentioning that all the
unsymmetrical benzamides except 3r underwent annulation
in a highly regioselective manner. Moreover, the ortho-
substituted benzamides were also explored under the
standard reaction condition. 2-Methyl-N-(1H-pyrrolo[2,3-
b]pyridin-1-yl)benzamide 1v and 2-fluoro-N-(1H-pyrrolo-
[2,3-b]pyridin-1-yl)benzamide 1w underwent desired annula-
tion to afford 3va and 3wa in 52 and 67% yield, respectively.
These findings reveal that the developed regioselective
annulation is facile for both electronically rich as well as
electronically poor benzamides. Indeed, the unsymmetrical
benzamides underwent annulation in a highly regioselective
manner to furnish their respective annulated adducts. After
successfully exploring the scope of electronically and
structurally distinct benzamides for the developed method-
ology, we further extended the scope with different 1,3-
diynes. Pleasingly, various aryl- and alkyl-substituted 1,3-
diynes (both electronically rich and poor) furnished
corresponding annulated adducts 3ab−3aj in 68−84% yield.
Notably, cyclopropyl-substituted 1,3-diyne 2j was also
efficiently obtained under this condition producing an
excellent yield of 3aj where the cyclopropyl fragment
remained intact. However, with unsymmetrical 1,3-diyne 2k,
a regioisomeric mixture (1:1) of products was obtained. Our
result with unsymmetrical 1,3-diyne is the same as that
obtained with cobalt by Nicholls and co-workers, but it is in
contrast to the results obtained by Glorius and co-workers
with rhodium. With rhodium high regioselectivity was
obtained with unsymmetrical 1,3-diynes. The regioselectivity
of the annulated adducts were confirmed unambiguously by
single-crystal X-ray analysis (for details see the Supporting
Information). In order to highlight the workability of the
developed annulation strategy, a gram-scale reaction was
carried out with 1a to give 3aa in 70% yield (Table 2).
annulation of N-(7-azaindole) benzamides with 1,3-diynes.
Accordingly, N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide 1a
and 1,4-diphenylbuta-1,3-diyne 2a were chosen as the model
substrate and coupling partner respectively in the presence of
5 mol % [Ru(p-cymene)Cl2]2 catalyst. When AgOTf was
used as an additive and Cu(OAc)2·H2O (30 mol %) was
used as an oxidant in DCE at 120 °C, annulation product
3aa was obtained in 16% yield (Table 1, entry 1). Various
other additives such as Ag2CO3, AgSbF6, AgNTf2, AgO-
COCF3, and AgBF4 were screened (Table 1, entries 2−6).
Among these additives, AgSbF6 gave a better yield of 3aa
(Table 1, entry 3). Subsequently, using the same additive,
different oxidants were tested (Table 1, entries 7−11).
However, all of them were found to be ineffective. Therefore,
keeping AgSbF6 as additive and Cu(OAc)2·H2O as oxidant,
we decided to increase the loading of oxidant (Table 1,
entries 12−15). Gratifyingly, the increase of Cu(OAc)2·H2O
up to 100 mol % enhanced the product yield up to 62%
(Table 1, entries 12−14). It is noteworthy that when 200
mol % Cu(OAc)2·H2O was employed, the yield of 3aa
significantly improved to 86% (Table 1, entry 15). However,
an attempt to replace the oxidant Cu(OAc)2·H2O by oxygen
with catalytic amount of Cu(OAc)2·H2O (20 mol %) resulted
in a loss of yield (Table 1, entry 16). Efforts to carry out the
reaction at a reduced temperature (100 and 80 °C) had a
deleterious effect on the reaction, giving the desired product
in 74 and 70% yield, respectively (Table 1, entries 17 and
18). Next, the feasibility of this annulation was assessed in
other solvents such as THF, 2-Me THF, TFE, HFIP, MeCN,
toluene, DMF, and trifluoro toluene. However, all of these
failed to give better yield than that of DCE (Table 1, entries
19−26).
Finally, to check the influence of AgSbF6 and Cu(OAc)2·
H2O, two control experiments were carried out. In the
absence of AgSbF6, 19% yield of 3aa was obtained, while
without Cu(OAc)2·H2O no product was detected. (Table 1,
entries 27 and 28). Therefore, the best optimized condition
was found to be 5 mol % [Ru(p-cymene)Cl2]2, 10 mol %
AgSbF6, along with 2.00 equiv of Cu(OAc)2·H2O in DCE
9429
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 1. Optimization of Reaction Conditions
b
entry
additive
AgOTf
Ag2CO3
AgSbF6
AgNTf2
AgOCOCF3
AgBF4
oxidant
solvent (0.2 M)
yield (%)
1
2
3
4
5
6
7
8
Cu(0Ac)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2
CuOTf
CuCO3
CuOCOCF3
CuO
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
O2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
2-Me THF
THF
TFE
HFIP
MeCN
toluene
DMF
trifluorotoluene
DCE
16
5
27
25
7
18
22
17
18
21
14
33
38
62
86 (83)
13
74
70
19
23
62
55
8
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
9
10
11
c
12
d
13
e
14
f
15
g
16
f h
17 ,
f i
18 ,
f
19
f
20
f
21
f
22
f
23
f
24
21
28
51
19
f
25
f
26
f
27
f
j
28
AgSbF6
DCE
nd
a
Unless otherwise specified, all reactions were carried out using [Ru(p-cymene)Cl2]2 (5 mol %), additive (10 mol %), 1a (0.20 mmol), 2a (0.10
b
c
mmol), and oxidant (30 mol %) in a solvent (0.20 M) for 12 h. Yield by NMR with 1,3,5-trimethoxybenzene as internal reference. Cu(OAc)2·
d
e
f
g
H2O (40 mol %). Cu(OAc)2·H2O (50 mol %). Cu(OAc)2·H2O (100 mol %). Cu(OAc)2·H2O (200 mol %). Cu(OAc)2·H2O (20 mol %).
h
i
j
Reaction was carried out at 100 °C. Reaction was carried out at 80 °C. nd = not detected. Isolated yield is given in the parentheses.
The synthetic diversifications of 3-alkynylated isoquino-
After successfully demonstrating the scope of diverse
benzamides and diynes and the synthesis applications on
the obtained products for this developed methodology, we
performed several mechanistic experiments to understand the
catalytic cycle.
lones (3) were explored. As shown in Scheme 3, Suzuki−
Miyaura coupling of 3la with phenyl boronic acid 4 provided
desired coupled product 5 in quantitative yield (Scheme
2a).10a Additionally, 3ma underwent Sonagashira coupling
with phenyl acetylene 6 to afford desired coupled product 7
in 82% yield (Scheme 2b).10b Furthermore, coupling of 3ma
with trimethylsilyl acetylene 8 furnished coupled product 9 in
80% yield (Scheme 2c).10c Silylated product 9 was subjected
to desilyllation10d (Scheme 2d) followed by coupling with
another molecule of 3ma to deliver symmetrical alkyne 11 in
78% yield (Scheme 2e).10b The obtained highly conjugated
molecule, 11, is expected to have very good photophysical
properties. Finally, alkyne 3aa underwent facile catalytic
hydrogenation to alkane with 10 mol % Pd/C and H2 gas to
furnish 80% of 3-alkylated isoquinolone 12 indicating
complete reduction of the alkyne to alkane (Scheme 2f).7i
The removal of the directing group of 3aa was also achieved
using excess SmI2 in THF, delivering 13 in 72% yield
(Scheme 2g).
Deuterium labeling and kinetic isotope effect experiments
were conducted. The deuterium labeling experiment of
benzamide 1a with D2O under the standard reaction
condition showed 90% deuterium incorporation at the
ortho-position of benzamide 1a-[d] in 57%, while the
deuterium incorporation at the C-2 and C-3 positions of 7-
azaindole were found to be 20 and 50%, respectively
(Scheme 3a). These results reveal the reversible nature of
the C−H metalation step. Similarly, the deuterium labeling
experiment of benzamide 1a with D2O in the absence of
additive AgSbF6 and catalyst [Ru-p-cymene)Cl2]2 were also
conducted. The level of deuterium incorporation in these two
cases is shown in the Scheme 3b,c. Overall, the ratio of ortho-
deuterated product is high in the presence of both catalyst
and AgSbF6. However, the absence of both Ru-catalyst and
9430
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 2. Scope of Benzamides and 1,3-Diynes for Regioselective Annulation
a
Unless otherwise specified, all reactions were carried out using [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (10 mol %), 1 (0.50 mmol), 2 (0.25
mmol), Cu(OAc)2·H2O (2 equiv) in DCE (0.10 M) at 120 °C for 12 h. Isolated yields are mentioned.
Ag additive resulted in the cleavage of the N−N bond of the
benzamide (Scheme 3d). An intermolecular competition and
parallel kinetic isotope effect experiment was carried out
using 1a/[D5]-1a with 2a. The experiment furnished kinetic
isotope effect (KH/KD) values of 2.33 and 1.17 for
competition and parallel experiments, respectively. The
small kinetic isotope effect value observed in parallel
experiment suggest that the C−H activation step may not
be the rate limiting step (Scheme 3e,f).14a
For further mechanistic insights, two intermolecular
competition experiments were conducted. Primarily, two
electronically different benzamides 1d and 1n were subjected
to the standard reaction conditions with diyne 2a which
afforded 3da/3na in 1.35:1 ratio (Scheme 4a). This
intermolecular competition reaction between electron-rich
and -poor benzamides revealed that the benzamide bearing
electron-donating group to be more reactive. These findings
are not in agreement with a concerted metalation−
deprotonation mechanism (CMD),14b but it can be better
explained in terms of an acetate-assisted internal electrophilic
substitution (BIES) mechanism.14c,e Furthermore, the com-
petition reaction between two different diynes 2b and 2g
with benzamide 1a produced 3ab/3ag in a 1:2 ratio (Scheme
4b). The results of the above competition experiment
between aryl and alkyl 1,3-diynes imply that the annulation
reaction is more favorable for alkyl-substituted diynes.
On the basis of the above mechanistic findings and
literature precedents,7c,b,11 a plausible catalytic cycle is shown
(Figure 2). Initially, cyclometalation of benzamide 1 with
active catalyst species I forms ruthenacycle II. Coordination
9431
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 2. Synthetic Diversifications and Deprotection of Annulated Adduct
Scheme 3. Mechanistic Studies with Labeled Substrates
of 1,3-diyne 2 to ruthenacycle II leads to the generation of
intermediate III. Subsequently, intermediate III undergoes
1,2-insertion with the coordinated 1,3-diyne 2 to furnish
intermediate IV. Reductive elimination from intermediate IV
afforded annulated adduct 3 along with the generation of
low-valent Ru(0). Afterward, Ru(0) is reoxidized to the active
catalytic species I in the presence of Cu(OAc)2·H2O to enter
into the next catalytic cycle.
CONCLUSION
■
In summary, we have demonstrated a straightforward and
highly regioselective synthetic strategy to access an array of
isoquinolone derivatives bearing bioactive 7-azaindole scaf-
9432
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 4. Competition Experiments
EXPERIMENTAL SECTION15
■
General Information. Reactions were performed using a
borosil-sealed tube vial under N2 atmosphere. Column chromatog-
raphy was done by using 230−400 mesh silica gel of Acme synthetic
chemicals company. A gradient elution was performed by using
distilled petroleum ether and ethyl acetate. TLC plates were
observed using UV light at 254 nm and vanillin. H and 13C NMR
1
were recorded on Bruker AV 400 and 700 MHz spectrometers using
CDCl3 as the deuterated solvent.12 Multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, quint = quintet, sept = septet, m =
multiplet, dd = doublet of doublet, dt = doublet of triplet, td =
triplet of doublet, and br = broad signal), integration, and coupling
constants (J) in hertz (Hz). HRMS signal analysis was performed
using a microTOF Q-II mass spectrometer. Reagents and starting
materials were purchased from Sigma-Aldrich, TCI, Avra,
Spectrochem, and other commercially available sources and used
without further purification unless otherwise noted. N-Amino-7-
azaindoles11 and 1,3-diynes13 were prepared according to the
literature reported procedure.
General Reaction Procedure A for the Preparation of
Benzamides (1). Benzamides (1) were prepared following the
previously reported procedure.3 EDC·HCl (1.20 mmol) and N,N-
diisopropylethylamine (2.50 mmol) were added to a solution
ofaromatic carboxylic acid (1.00 mmol), N-amino-7-azaindole (1.0
mmol), and HOBt (1.20 mmol) in dimethylformamide (3.00 mL)
and stirred for 12 h at room temperature. After the completion, the
reaction was diluted with EtOAc (2 × 30 mL) and then washed
with water (5.00 mL) and brine solution (5.00 mL), dried over
Na2SO4, filtered, and concentrated in vacuum. The resulting residue
was purified by column chromatography to give pure benzamides
(1).
General Reaction Procedure B for Regioselective ortho-
C(sp2)−H Activation/Annulation of N-(7-Azaindole)-
benzamides with 1,3-Diynes. A flame-dried 15 mL screw-capped
vial equipped with a magnetic stir bar was charged with benzamide
1 (0.20 mmol, 2 equiv), 1,3-diyne 2 (0.10 mmol, 1.00 equiv), Ru(p-
cymene)Cl2]2 (0.005 mmol), AgSbF6 (0.01 mmol), Cu(OAc)2·H2O
(0.20 mmol, 2.00 equiv), and DCE (500 μL). Then the contents
were allowed to stir at 120 °C in a preheated aluminum block for
12 h. The completion of the reaction was monitored by TLC. Upon
completion of the reaction, the tube was cooled down to room
temperature, and the reaction mixture was diluted with 5.00 mL of
dichloromethane and filtered with a plug Celite bed, followed by
washing with 20.00 mL of dichloromethane. The combined residue
was concentrated under reduced pressure, and the resulting crude
product was purified by silica gel column chromatography using
hexane/ethyl acetate (2:8) to afford desired product 3.
General Reaction Procedure C for Regioselective ortho-
C(sp2)−H Activation/Annulation of N-(7-Azaindole)-
benzamides with 1,3-Diynes in 1 g Scale. A flame-dried
15.00 mL screw-capped vial equipped with a magnetic stir bar was
charged with benzamide 1a (9.89 mmol, 2.00 equiv), 1,3-diyne 2a
(4.94 mmol, 1.00 equiv), Ru(p-cymene)Cl2]2 (0.25 mmol), AgSbF6
(0.49 mmol), Cu(OAc)2·H2O (9.88 mmol, 2.00 equiv), and DCE
(20.00 mL). Then the contents were allowed to stir at 120 °C in a
preheated aluminum block for 12 h. The completion of the reaction
was monitored by TLC. Upon completion of the reaction, the tube
was cooled down to room temperature, and the reaction mixture
was diluted with 180.00 mL of dichloromethane and filtered with a
plug of Celite, followed by washing with 300.00 mL of dichloro-
methane. The combined residue was concentrated under reduced
pressure, and the resulting crude product was purified by silica gel
column chromatography using hexane/ethyl acetate (2:8) to afford
desired product 3aa (1.51 g) in 70% yield.
Figure 2. Proposed catalytic cycle.
fold. This methodology worked efficiently for diverse amides
and 1,3-diynes which showcase the potential of N-amino-7-
azaindole as a useful N,N-bidentate directing group. More-
over, the obtained annulated products have been subjected to
numerous other transformations resulting in synthetically
valuable molecules. Along with the excellent functional group
tolerance, high regioselectivity has also been achieved with
unsymmetrical benzamides. The preliminary mechanistic
findings revealed noninvolvement of the C−H activation in
the rate limiting step of the reaction.
General Reaction Procedure D for Arylation of 3la. A
mixture of 3la (0.10 mmol, 1.00 equiv), phenylboronic acid 4 (1.5
equiv), Na2CO3 (10.00 equiv), and Pd(PPh3)4 (10.00 mol %) in
THF (1.00 mL) and H2O (0.25 mL) was stirred at 70 °C in a
preheated aluminum block for 12 h under N2 atmosphere. The
mixture was added with H2O (10.00 mL) and extracted with
9433
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
CH2Cl2. The combined organic phase was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (EtOAc/hexane) to afford product 5 in
93% yield.
General Reaction Procedure E for Alkynylation of 3ma
with Ethynylbenzene. A mixture of 3ma (0.10 mmol, 1.00 equiv),
phenylacetylene 6 (1.50 equiv), CuI (50 mol %), and Pd(PPh3)4
(5.00 mol %) in THF (0.50 mL) and Et3N (0.50 mL) was stirred at
50 °C in a preheated aluminum block for 4 h under N2 atmosphere.
The reaction mixture was poured into a saturated NH4Cl solution
and extracted with CH2Cl2. The combined organic phase was dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by chromatography on silica gel (EtOAc/hexane) to
afford product 7 in 82% yield.
General Reaction Procedure F for Alkynylation of 3ma
with Ethynyltrimethylsilane. A mixture of 3ma (0.10 mmol),
ethynyltrimethylsilane 8 (0.15 mmol), PdCl2(PPh3)2 (0.04 mmol),
and CuI (0.04 mmol) were mixed in THF (1.00 mL) containing
NEt3 (2.00 equiv). The resulting solution was stirred at room
temperature for 24 h. After the reaction was finished, ethyl acetate
(10.00 mL) was poured into the mixture. The resulting mixture was
then washed with brine, extracted with ethyl acetate, and dried over
anhydrous Na2SO4. After filtration and removal of the solvents, the
residue was subjected to flash column chromatography on silica gel
(230−400 mesh) using (EtOAc/hexane) as eluent to afford silylated
alkynes 9 in 80% yield.
General Reaction Procedure G for Desilylation of 9. A
mixture of 9 (0.10 mmol), K2CO3 (0.20 mmol), MeOH (0.40 mL),
and THF (0.40 mL) was stirred at room temperature for 4 h. Then,
the reaction mixture was extracted with ethyl acetate and washed
with brine. By evaporating the solvent, the obtained residue was
subjected to flash column chromatography on silica gel (230−400
mesh) using (EtOAc/hexane) as eluent to afford desilylated alkyne
10 in 94% yield.
with 10.00 mL of dichloromethane and filtered through a Celite
pad. The filtered solution was concentrated under reduced pressure.
Then, the residue was purified by column chromatography with
EtOAc/hexane as eluent. The extent of H/D exchange was
calculated via 1H NMR (for spectra, see the Supporting
Information).
General Reaction Procedure L for Deuterium Labeling
Experiment in the Absence of AgSbF6. A flame-dried 15.00 mL
screw-capped vial equipped with a magnetic stir bar was charged
with benzamide 1a (0.10 mmol), Ru(p-cymene)Cl2]2 (0.005 mmol),
Cu(OAc)2·H2O (2.00 equiv), D2O (10.00 equiv), and DCE (500
μL). The contents were allowed to stir at 140 °C in a preheated
aluminum block for 12 h. Then the contents were allowed to cool
down to room temperature. Later, the reaction mixture was diluted
with 10.00 mL of dichloromethane and filtered through a Celite
pad. The filtered solution was concentrated under reduced pressure.
Then, the residue was purified by column chromatography with
EtOAc/hexane as eluent. The extent of H/D exchange was
calculated via 1H NMR (for spectra, see the Supporting
Information).
General Reaction Procedure M for Deuterium Labeling
Experiment in the Absence of Ru(p-cymene)Cl2]2. A flame-
dried 15.00 mL screw-capped vial equipped with a magnetic stir bar
was charged with benzamide 1a (0.10 mmol), AgSbF6 (0.01 mmol),
Cu(OAc)2·H2O (2.00 equiv), D2O (10.00 equiv), and DCE (500
μL). The contents were allowed to stir at 140 °C in a preheated
aluminum block for 12 h. Then the contents were allowed to cool
down to room temperature. Later, the reaction mixture was diluted
with 10.00 mL of dichloromethane and filtered through a Celite
pad. The filtered solution was concentrated under reduced pressure.
Then, the residue was purified by column chromatography with
EtOAc/hexane as eluent. The extent of H/D exchange was
calculated via 1H NMR (for spectra, see the Supporting
Information).
General Reaction Procedure H for Alkynylation of 3ma
with 10. A mixture of 3ma (0.10 mmol, 1.00 equiv), terminal
alkyne 10 (1.50 equiv), CuI (50 mol %), and Pd(PPh3)4 (5.00 mol
%) in THF (0.50 mL) and Et3N (0.50 mL) was stirred at at 50 °C
in a preheated aluminum block for 6 h under N2 atmosphere. The
reaction mixture was poured into a saturated NH4Cl solution and
extracted with CH2Cl2. The combined organic phase was dried over
MgSO4 and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (EtOAc/hexane) to afford
product 11 in 78% yield.
General Reaction Procedure I for Reduction of 3aa. A
mixture of product 3aa (0.10 mmol) and Pd/C (0.01 mmol) was
taken in a 25.00 mL round-bottomed flask. Next, 3.50 mL of ethyl
acetate was added, and H2 gas was passed through the setup for 12
h at room temperature. The reaction was checked for complete
conversion by TLC, and product 12 was purified using silica gel
column chromatography to afford 12 in 80% yield (ethyl acetate/
hexane).
General Reaction Procedure J for the Removal of the
Directing Group. An oven-dried 25 mL two-necked, round-
bottomed flask was charged with 3aa (0.10 mmol, 1 equiv). After
purging with argon three times, 5 mL of fresh distilled THF was
added, followed by SmI2 (0.1 M in THF, 20 equiv) was added
dropwise at 0 °C. After 5 min, the mixture was warmed to room
temperature and stirred overnight. After that, the mixture was
quenched with 5 mL of saturated aqueous Na2S2O3 and extracted
with DCM, dried over Na2SO4, filtered, and concentrated under
reduced pressure, yielding 13 via column chromatography.
General Reaction Procedure K for Deuterium Labeling
Experiment. A flame-dried 15.00 mL screw-capped vial equipped
with a magnetic stir bar was charged with benzamide 1a (0.10
mmol), Ru(p-cymene)Cl2]2 (0.005 mmol), AgSbF6 (0.01 mmol),
Cu(OAc)2·H2O (2.00 equiv), D2O (10.00 equiv), and DCE (500
μL). The contents were allowed to stir at 140 °C in a preheated
aluminum block for 12 h. Then the contents were allowed to cool
down to room temperature. Next, the reaction mixture was diluted
General reaction procedure N for Deuterium Labeling
Experiment in the Absence of Ru(p-cymene)Cl2]2 and
AgSbF6. A flame-dried 15.00 mL screw-capped vial equipped with
a magnetic stir bar was charged with benzamide 1a (0.10 mmol),
Cu(OAc)2·H2O (2.00 equiv), D2O (10.00 equiv), and DCE (500
μL). The contents were allowed to stir at 140 °C in a preheated
aluminum block for 12 h. Then the contents were allowed to cool
down to room temperature. Later, the reaction mixture was diluted
with 10.00 mL of dichloromethane and filtered through a Celite
pad. The filtered solution was concentrated under reduced pressure.
Then, the residue was purified by column chromatography with
EtOAc/hexane as eluent. The extent of H/D exchange was
calculated via 1H NMR (for spectra, see the Supporting
Information).
General Reaction Procedure O for Intermolecular Com-
petition KIE for the Reaction. A flame-dried 5.00 mL screw
capped vial equipped with a magnetic stir bar was charged with
benzamide 1a (0.05 mmol), [D5]-1a (0.05 mmol), 1,4-diphenylbuta-
1,3-diyne (2a, 0.05 mmol, 1 equiv), [Ru(p-cymene)Cl2]2 (5 mol %),
AgSbF6 (10 mol %), Cu(OAc)2·H2O (0.10 mmol, 2 equiv), and
DCE (0.25 mL). The contents were allowed to stir at 120 °C in a
preheated aluminum block for 25 min. After 25 min, the reaction
tube was cooled down to room temperature, and the reaction
mixture was diluted with 1.00 mL of dichloromethane and filtered
through a small plug of Celite, followed by washing with 3 mL of
dichloromethane. Then, the residue was purified by column
chromatography with EtOAc/hexane as eluent to afford the desired
product [D4/H4]-3aa. The kinetic isotopic value (kH/kD ≈ 2.33)
1
was calculated from the H NMR of the mixture [D4/H4]-3aa (for
spectra, see the Supporting Information).
General Reaction Procedure P for Parallel Reaction KIE for
the Reaction. By following the general procedure, 3 sets of parallel
experiments were set. A flame-dried 5.00 mL screw capped vial
equipped with a magnetic stir bar was charged with H5/[D]5-1a
(2.00 equiv), 1,4-diphenylbuta-1,3-diyne (2a, 0.05 mmol, 1.00
equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (10 mol %),
9434
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Cu(OAc)2·H2O (0.10 mmol, 2.00 equiv), and DCE (0.25 mL). The
reactions were carried out at 4 min time intervals (4, 8, and 12 min)
at 120 °C in a preheated aluminum block. The product yields were
HRMS (ESI) m/z: [M + H]+ Calcd for C15H11F3N3O: 306.0854.
Found: 306.0852.
3-Fluoro-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (1r). The
title compound was prepared according to general procedure A. The
crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 1r (196 mg) in 77% yield.
Physical state: off-white solid, mp: 180−183 °C, Rf value: 0.50 (40%
EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 13.32 (s, 1H),
8.27 (dd, J = 4.8, 1.2 Hz, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.79
(d, J = 8.0 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 3.6 Hz,
1H), 7.20−7.14 (m, 1H), 7.11−7.06 (m, 2H), 6.47 (d, J = 3.6 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 165.9 (d, JC−F = 2 Hz),
162.7 (d, JC−F = 246 Hz), 146.4, 142.1, 131.1 (d, JC−F = 7 Hz),
130.8, 130.6, 130.4 (d, JC−F = 8 Hz), 123.0 (d, JC−F = 3 Hz), 120.3,
119.5 (d, JC−F = 21 Hz), 117.2, 115.4 (d, JC−F = 24 Hz), 99.9. 19F
NMR (376 MHz, CDCl3): δ −111.5. IR (KBr, cm−1): 3428, 3053,
2927, 1687, 1544. HRMS (ESI) m/z: [M + H]+ Calcd for
C14H11FN3O: 256.0881. Found: 256.0888.
1
calculated from the H NMR analysis of the crude reaction mixture
using 1,3,5-trimethoxy benzene as an internal standard. The KIE
value was calculated from the obtained slopes of two lines (for
spectra, see the Supporting Information).
General Reaction Procedure Q for Intermolecular Com-
petition Reaction between Two Different Benzamides. A
flame-dried 5.00 mL screw-capped vial equipped with a magnetic stir
bar was charged with two different benzamides (1d, 0.10 mmol, 2.00
equiv), (1n, 0.10 mmol, 2.00 equiv), 1,4-diphenylbuta-1,3-diyne (2a,
0.05 mmol, 1.00 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6
(10 mol %), Cu(OAc)2·H2O (0.10 mmol, 2.00 equiv), and DCE
(0.25 mL). The contents were allowed to stir at 120 °C in a
preheated aluminum block for 12 h. Upon completion of the
standard reaction time, the reaction tube was cooled to room
temperature, and the reaction mixture was diluted with 1 mL of
dichloromethane and filtered through a Celite bed, followed by
washing with 3.00 mL of dichloromethane. The filtered solution was
concentrated under reduced pressure. The ratio of two products
3-Chloro-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (1s). The
title compound was prepared according to general procedure A. The
crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 1s (212 mg) in 78% yield.
Physical state: white solid, mp: 208−211 °C, Rf value: 0.50 (40%
1
3da/3na (1.35:1) was calculated from the H NMR analysis of the
crude product using 1,3,5-trimethoxy benzene as the internal
standard (for spectra, see the Supporting Information).
1
EtOAc/hexane). H NMR (400 MHz, DMSO-d6): 11.99 (s, 1H),
8.29 (dd, J = 4.8, 1.2 Hz, 1H), 8.10−8.07 (m, 2H), 8.01 (d, J = 7.6
Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69−7.65 (m, 2H), 7.22 (dd, J
= 7.6, 4.4 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H). 13C{1H} NMR (100
MHz, DMSO-d6): δ 165.9, 147.1, 144.2, 134.6, 134.4, 133.2, 131.8,
131.3, 130.0, 128.4, 127.4, 119.5, 117.5, 96.6. IR (KBr, cm−1): 3061,
2853, 1734, 1677, 1551. HRMS (ESI) m/z: [M + H]+ Calcd for
C14H11ClN3O: 272.0585. Found: 272.0584.
General Reaction Procedure R for Intermolecular Com-
petition Reaction between Two Different Diynes. A flame-
dried 5.00 mL screw-capped vial equipped with a magnetic stir bar
was charged with benzamide (1a, 0.10 mmol, 2.00 equiv), two
different diynes (2b, 0.05 mmol, 1.00 equiv; 2g, 0.05 mmol, 1.00
equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (10 mol %),
Cu(OAc)2·H2O (0.10 mmol, 2.00 equiv), and DCE (0.25 mL). The
contents were allowed to stir at 120 °C in a preheated aluminum
block for 12 h. Upon completion of the standard reaction time, the
reaction tube was cooled to room temperature, and the reaction
mixture was diluted with 1.00 mL of dichloromethane and filtered
through Celite bed, followed by washing with 3.00 mL of
dichloromethane. The filtered solution was concentrated under
reduced pressure. The ratio of two products 3ab/3ag (1:2) was
3-Nitro-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (1t). The
title compound was prepared according to general procedure A.
The crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 1t (240 mg) in 85% yield.
Physical state: white solid, mp: 189−192 °C, Rf value: 0.40 (60%
1
EtOAc/hexane). H NMR (400 MHz, DMSO-d6): δ 12.27 (s, 1H),
8.88 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.47 (d, J = 7.6 Hz, 1H),
8.30 (d, J = 4.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.95 (t, J = 8.0
Hz, 1H), 7.69 (d, J = 3.6 Hz, 1H), 7.23 (dd, J = 8.0, 4.8 Hz, 1H),
6.64 (d, J = 3.6 Hz, 1H). 13C{1H} NMR (100 MHz, DMSO-d6): δ
165.4, 148.8, 147.1, 144.2, 135.0, 134.0, 131.6, 131.2, 130.1, 128.0,
123.4, 119.5, 117.7, 99.8. IR (KBr, cm−1): 3095, 2870, 1684, 1651,
1538. HRMS (ESI) m/z: [M + H]+ Calcd for C14H11N4O3:
283.0826. Found: 283.0825.
1
calculated from the H NMR analysis of the crude product using
1,3,5-trimethoxy benzene as the internal standard (for spectra, see
the Supporting Information).
Experimental Characterization Data for the New Benza-
mides. N-(1H-Pyrrolo[2,3-b]pyridin-1-yl)benzo[d][1,3]dioxole-5-
carboxamide (1g). The title compound was prepared according
to general procedure A. The crude reaction mixture was purified by
column chromatography using silica gel (230−400 mesh), giving 1g
(248 mg) in 88% yield. Physical state: off-white solid, mp: 183−185
°C, Rf value: 0.40 (50% EtOAc/hexane). 1H NMR (400 MHz,
CDCl3): δ 12.92 (br, 1H), 8.25 (d, J = 4.0 Hz, 1H), 7.89 (d, J = 7.6
Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.21
(d, J = 1.6 Hz, 1H), 7.09−7.05 (m, 1H), 6.64 (d, J = 8.4 Hz, 1H),
6.46 (d, J = 3.6 Hz, 1H), 5.97 (s, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 166.4, 151.3, 147.9, 146.4, 142,0, 130.8, 130.7, 125.3,
122.7, 120.3, 117.0, 108.4, 108.0, 101.9, 49.6. IR (KBr, cm−1): 3098,
3057, 3008, 2986, 1682, 1673, 1574, 1494, 1275, 1130. HRMS
(ESI) m/z:[M + H]+ Calcd for C15H12N3O3 282.0873. Found:
282.0880.
N-(1H-Pyrrolo[2,3-b]pyridin-1-yl)-3-(trifluoromethyl)benzamide
(1u). The title compound was prepared according to general
procedure A. The crude reaction mixture was purified by column
chromatography using silica gel (230−400 mesh) giving 1u (256
mg) in 84% yield. Physical state: colorless solid, mp: 181−184 °C,
1
Rf value: 0.46 (50% EtOAc/hexane). H NMR (400 MHz, CDCl3):
δ 13.42 (br, 1H), 8.29 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 8.0 Hz,
2H), 7.95 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.33−7.25
(m, 2H), 7.14 (dd, J = 8.0, 4.8 Hz, 1H), 6.51 (d, J = 3.6 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 146.6, 142.2, 131.7,
131.3 (q, JC−F = 33.0 Hz), 131.0, 130.6, 130.5, 129.4, 129.1 (q, JC−F
= 4.0 Hz), 125.4 (q, JC−F = 4.0 Hz), 123.7 (q, JC−F = 271.0 Hz),
119.9, 117.3, 100.1. 19F NMR (376 MHz, CDCl3): δ −63.0. IR
(KBr, cm−1): 2984, 1737, 1639, 1547. HRMS (ESI) m/z: [M + H]+
Calcd for C15H11F3N3O: 306.0854. Found: 306.0853.
2-Methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (1v). The
title compound was prepared according to general procedure A. The
crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 1v (206 mg) in 82% yield.
Physical state: off-white solid, mp: 139−142 °C, Rf value: 0.50 (40%
EtOAc/hexane). 1H NMR (400 MHz, CDCl3): δ 10.80 (s, 1H),
8.18 (d, J = 4.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6
Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 3.6 Hz, 1H), 7.13−
7.06 (m, 2H), 7.02 (dd, J = 7.6, 4.8 Hz, 1H), 6.40 (d, J = 3.2 Hz,
1H), 2.32 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.6,
N-(1H-Pyrrolo[2,3-b]pyridin-1-yl)-4-(trifluoromethyl)benzamide
(1p). The title compound was prepared according to general
procedure A. The crude reaction mixture was purified by column
chromatography using silica gel (230−400 mesh) giving 1p (250
mg) in 82% yield. Physical state: off-white solid, mp: 154−157 °C,
1
Rf value: 0.44 (50% EtOAc/hexane). H NMR (400 MHz, CDCl3):
δ 8.30 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.97 (d, J =
8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 4.0 Hz, 1H),
7.15 (dd, J = 7.6, 4.8 Hz, 1H), 6.55 (d, J = 3.6 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ 165.7, 146.5, 142.2, 134.1, 133.9 (q,
JC−F = 7.0 Hz), 131.1, 130.6, 128.3, 125.8 (q, JC−F = 4.0 Hz), 123.8
(q, JC−F = 271.0 Hz), 120.5, 117.4, 100.2. 19F NMR (376 MHz,
CDCl3): δ −63.3. IR (KBr, cm−1): 3054, 2286, 1686, 1673, 1574.
9435
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
146.5, 143.1, 138.2, 132.2, 131.5, 131.1, 130.07, 130.03, 127.7,
125.8, 119.7, 117.1, 96.6, 20.4. IR (KBr, cm−1): 3055, 2847, 1682,
1590, 1518. HRMS (ESI) m/z: [M + H]+ Calcd for C15H14N3O:
252.1131. Found: 252.1139.
2963, 2870, 2207, 1686, 1609, 1551. HRMS (ESI) m/z: [M + H]+
Calcd for C34H28N3O: 494.2227. Found: 494.2234.
6-Methoxy-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3da). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3da (38 mg) in 82% yield. Physical state:
brown crystalline solid, mp: 224−227 °C, Rf value: 0.36 (30%
2-Fluoro-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (1w). The
title compound was prepared according to general procedure A. The
crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 1w (202 mg) in 79% yield.
Physical state: light-yellow solid, mp: 179−182 °C, Rf value: 0.40
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ8.46 (d, J = 8.8
1
Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 7.7, 0.9 Hz, 1H),
7.60 (d, J = 6.3 Hz, 1H), 7.52−7.44 (m, 5H), 7.16−7.09 (m, 3H),
7.05 (t,J = 7.7 Hz, 2H), 6.77 (d, J = 2.3 Hz, 1H), 6.71 (d, J = 3.8
Hz, 1H), 6.52 (d, J = 7.2 Hz, 2H), 3.77 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 163.8, 160.6, 147.0, 144.7, 139.1, 135.7,
131.6, 131.4, 131.4, 131.1, 129.8, 129.2, 129.1, 128.7, 128.6, 128.5,
128.3, 126.9, 125.0, 121.6, 120.1, 119.2, 117.6, 116.5, 108.7, 100.7,
98.7, 81.2, 55.8. IR (KBr, cm−1): 2967, 2974, 2211, 1677, 1640,
1554. HRMS (ESI) m/z: Calcd for C31H21N3NaO2: 490.1531.
Found: 490.1525.
6-(Methylthio)-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ea). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ea (37 mg) in 77% yield. Physical state:
brown solid, mp: 210−213 °C, Rf value: 0.42 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.4 Hz, 1H), 8.37 (dd,
J = 4.8, 1.2 Hz, 1H), 8.04 (dd, J = 8.0, 1.6 Hz, 1H), 7.63−7.61 (m,
1H), 7.53−7.49 (m, 4H), 7.47 (d, J = 3.6 Hz, 1H), 7.39 (dd, J =
8.4, 2.0 Hz, 1H), 7.19−7.16 (m, 3H), 7.08 (t, J = 7.6 Hz, 2H), 6.74
(d, J = 3.6 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 160.7, 147.0, 146.7, 144.8,
137.3, 135.4, 131.7, 131.5, 131.2, 129.8, 129.4, 129.3, 129.0, 128.8,
128.6, 128.6, 128.3, 127.1, 125.5, 124.7, 123.0, 121.6, 121.5, 119.2,
117.6, 100.8, 98.9, 81.1, 15.1. IR (KBr, cm−1): 2922, 2209, 1682,
1651, 1591, 1558. HRMS (ESI) m/z: [M + Na]+ Calcd for
C31H21N3NaOS: 506.1303. Found: 506.1297.
(40% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 10.40 (s,
1H), 8.29 (d, J = 4.2 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.88 (d, J =
7.7 Hz, 1H), 7.49 (q, J = 7.0 Hz, 1H), 7.28 (d, J = 3.5 Hz, 1H),
7.19 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 9.8 Hz, 1H), 7.08 (t, J = 5.6
Hz, 1H), 6.49 (d, J = 2.8 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 163.9 (d, JC−F = 5.2 Hz), 161.0 (d, JC−F = 250 Hz),
146.6, 143.7, 134.7 (d, JC−F = 8.8 Hz), 132.5 (d, JC−F = 1.7 Hz),
129.9, 129.7, 125.1 (d, JC−F = 3.5 Hz), 119.5, 118.9 (d, JC−F = 12.3
Hz), 117.2, 116.5 (d, JC−F = 22.9 Hz), 99.9. 19F NMR (376 MHz,
CDCl3): δ −109.3. IR (KBr, cm−1): 3066, 2961, 1677, 1614, 1583.
HRMS (ESI) m/z: [M + H]+ Calcd for C14H11FN3O: 256.0881.
Found: 256.0881.
Experimental Characterization Data for the Annulated
Compounds. 4-Phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3aa). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3aa (36 mg) in 83% yield. Physical state:
light-brown solid, mp: 180−183 °C, Rf value: 0.45 (30% EtOAc/
1
hexane). H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 8.0 Hz, 1H),
8.35 (dd, J = 4.8, 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.2 Hz, 1H),
7.65−7.45 (m, 8H), 7.40 (d, J = 8.0 Hz, 1H), 7.16−7.12 (m, 2H),
7.05 (t, J = 7.6 Hz, 2H), 6.72 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 7.2
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.9, 146.9, 144.7,
137.0, 135.5, 133.5, 131.6, 131.4, 131.2, 129.8, 129.2, 129.2, 129.0,
128.7, 128.5, 128.5, 128.3, 126.4, 126.4, 126.4, 125.4, 121.5, 119.2,
117.6, 100.8, 98.7, 81.1. IR (KBr, cm−1): 3057, 2209, 1696, 1677,
1642. HRMS (ESI) m/z: [M + Na]+ Calcd for C30H19N3NaO:
460.1426. Found: 460.1420.
6-Methyl-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ba). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ba (37 mg) in 82% yield. Physical state:
brown solid, mp: 211−216 °C, Rf value: 0.42 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.0 Hz, 1H), 8.35 (dd,
J = 4.4, 0.8 Hz, 1H), 8.00 (dd, J = 8.0, 1.2 Hz, 1H), 7.59 (d, J = 7.6
Hz, 1H), 7.52−7.48 (m, 4H), 7.44 (d, J = 3.6 Hz, 1H), 7.37 (d, J =
8.0 Hz, 1H), 7.16−7.12 (m, 3H), 7.05 (t, J = 8.0 Hz, 2H), 6.71 (d,
J = 3.6 Hz, 1H), 6.51 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 160.9, 146.9, 144.7, 144.4, 137.0,
135.7, 131.7, 131.4, 131.2, 129.8, 129.8, 129.2, 129.2, 129.1, 128.7,
128.5, 128.5, 128.3, 126.4, 126.2, 125.3, 124.2, 121.6, 119.2, 117.6,
100.8, 98.6, 81.2, 22.3. IR (KBr, cm−1): 2925, 2848, 2206, 1680,
1651, 1616, 1556. HRMS (ESI) m/z: [M + Na]+ Calcd for
C31H21N3NaO: 474.1582. Found: 474.1576.
6,7-Dimethoxy-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1yl)isoquinolin 1(2H)-one (3fa). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3fa (39 mg) in 77% yield. Physical state:
brown crystalline solid, mp: 259−261 °C, Rf value: 0.50 (30%
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.35 (dd, J = 4.8,
1.2 Hz, 1H), 8.02 (dd, J = 7.6, 1.2 Hz, 1H), 7.92 (s, 1H), 7.63−
7.61 (m, 1H), 7.53−7.42 (m, 5H), 7.18−7.12 (m, 2H), 7.05 (t, J =
8.0 Hz, 2H), 6.76 (s, 1H), 6.71 (d, J = 4.0 Hz, 1H), 6.53 (d, J = 8.0
Hz, 2H), 4.00 (s, 3H), 3.78 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 160.3, 154.1, 150.2, 147.0, 144.7, 135.9, 132.4, 131.6,
131.3, 131.1, 129.7, 129.1, 129.0, 128.7, 128.6, 128.6, 128.3, 125.0,
121.7, 120.5, 119.2, 117.6, 109.2, 106.9, 100.7, 98.1, 81.3, 56.6, 56.3.
IR (KBr, cm−1): 2930, 2211, 1664, 1639, 1610, 1510. HRMS (ESI)
m/z: [M + Na]+ Calcd for C32H23N3NaO3: 520.1637. Found:
520.1631.
9-Phenyl-8-(phenylethynyl)-7-(1H-pyrrolo[2,3-b]pyridin-1-yl)-
[1,3]dioxolo[4,5-f ]isoquinolin-6(7H)-one (3ga). The title com-
pound was prepared according to general procedure B. The crude
reaction mixture was purified by column chromatography using silica
gel (230−400 mesh) giving 3ga (38 mg) in 79% yield. Physical
state: yellowish brown solid, mp: 284−287 °C, Rf value: 0.55 (40%
6-(tert-Butyl)-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ca). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ca (40 mg) in 80% yield. Physical state:
light brown solid, mp: 223−225 °C, Rf value: 0.48 (30% EtOAc/
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 4.8
Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.57
(d, J = 4.0 Hz, 1H), 7.49−7.41 (m, 5H), 7.16−7.12 (m, 2H), 7.08−
7.02 (m, 3H), 6.70 (d, J = 3.6 Hz, 1H), 6.49 (d, J = 7.6 Hz, 2H),
5.86 (d, J = 4.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
160.3, 152.1, 146.9, 144.7, 142.9, 136.7, 131.4, 131.2, 130.8, 1298,
129.2, 129.1, 128.3, 128.1, 127.8, 127.7, 125.4, 121.5, 121.4, 120.9,
120.8, 119.2, 110.0, 102.3, 100.7, 98.9, 81.1. IR (KBr, cm−1): 3159,
2957, 2851, 2361, 2211, 1698, 1683, 1557. HRMS (ESI) m/z: [M +
H]+ Calcd for C31H20N3O3: 482.1499. Found: 482.1489.
1
hexane). H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 8.4 Hz, 1H),
8.35 (d, J = 4.2, Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.62−7.60 (m,
2H), 7.52−7.44 (m, 6H), 7.40 (s, 1H), 7.16−7.12 (m, 2H), 7.05 (t,
J = 7.6 Hz, 2H), 6.71 (d, J = 4.0 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H),
1.27 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.8, 157.3,
146.9, 144.7, 136.8, 135.7, 131.7, 131.4, 131.2, 129.8, 129.1, 129.1,
129.0, 128.6, 128.5, 128.5, 128.3, 126.3, 126.2, 125.8, 124.1, 122.7,
121.7, 119.2, 117.6, 100.7, 98.4, 81.3, 35.7, 31.3. IR (KBr, cm−1):
9436
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4-Phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-
benzo[g]isoquinolin-1(2H)-one (3ha). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ha (31 mg) in 63% yield. Physical state:
brown solid, mp: 260−263 °C, Rf value: 0.60 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.36 (dd, J = 4.8, 1.6
Hz, 1H), 8.09−8.02 (m, 2H), 7.83−7.82 (m, 2H), 7.68 (d, J = 6.8
Hz, 1H), 7.60−7.52 (m, 6H), 7.49 (d, J = 3.6 Hz, 1H), 7.18−7.13
(m, 2H), 7.06 (t, J = 7.6 Hz, 2H), 6.73 (d, J = 3.6 Hz, 1H), 6.53
(d, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.5,
146.1, 144.8, 136.0, 135.9, 132.9, 132.4, 131.8, 131.4, 131.3, 131.0,
129.8, 129.8, 129.2, 129.1, 129.0, 128.8, 128.7, 128.6, 128.6, 128.3,
127.3, 125.9, 125.7, 125.2, 124.2, 121.8, 119.3, 117.6, 100.8, 98.7,
81.5. IR (KBr, cm−1): 3159, 2957, 2851, 2361, 2211, 1698, 1683,
1557. HRMS (ESI) m/z: [M + Na]+ Calcd for C34H21N3NaO:
510.1582. Found: 510.1576.
6-Bromo-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3la). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3la (38 mg) in 74% yield. Physical state:
off-white solid, mp: 248−250 °C, Rf value: 0.45 (30% EtOAc/
1
hexane). H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 8.4 Hz, 1H),
8.35 (dd, J = 4.8, 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.6 Hz, 1H), 7.64
(dd, J = 8.8, 1.6 Hz, 1H), 7.59−7.49 (m, 6H), 7.44 (d, J = 4.0 Hz,
1H), 7.16 (dd, J = 8.0, 5.2 Hz, 2H), 7.06 (t, J = 7.6 Hz, 2H), 6.72
(d, J = 3.6 Hz, 1H), 6.53−6.52 (d, J = 8.0 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 160.4, 146.8, 144.9, 138.5, 134.9, 131.6,
131.5, 131.5, 131.1, 130.9, 129.9, 129.5, 129.2, 129.0, 128.9, 128.8,
128.8, 128.4, 127.8, 125.1, 124.2, 121.3, 119.2, 117.8, 119.2, 101.0,
99.5, 80.8. IR (KBr, cm−1): 2990, 2943, 2354, 2253, 1658, 1633,
1554. HRMS (ESI) m/z: [M + H]+ Calcd for C30H19BrN3O:
516.0711. Found: 516.0703.
6-Iodo-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-
1-yl)isoquinolin-1(2H)-one (3ma). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ma (44 mg) in 79% yield. Physical state:
brown solid, mp: 231−233 °C, Rf value: 0.43 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 8.34 (dd, J = 4.8, 1.2 Hz, 1H), 8.20
(d, J = 8.4 Hz, 1H), 8.02 (dd, J = 7.6, 1.2 Hz, 1H), 7.86 (dd, J =
8.4, 1.2 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.58−7.48 (m, 5H), 7.43
(d, J = 4.0 Hz, 1H), 7.16 (dd, J = 7.6, 5.2 Hz, 2H), 7.06 (t, J = 7.2
Hz, 2H), 6.72 (d, J = 4.0 Hz, 1H), 6.51 (d, J = 8.0 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 160.6, 146.8, 144.8, 138.3,
137.3, 135.1, 134.9, 131.6, 131.5, 131.1, 130.6, 129.9, 129.5, 128.9,
128.8, 128.8, 128.8, 128.4, 128.4, 127.6, 125.5, 124.0, 121.3, 119.2,
117.8, 102.0, 101.0, 99.5, 80.9. IR (KBr, cm−1): 2916, 2848, 2208,
1698, 1661, 1537. HRMS (ESI) m/z: [M + Na]+ Calcd for
C30H18IN3NaO: 586.0392. Found: 586.0387.
7-Phenyl-6-(phenylethynyl)-5-(1H-pyrrolo[2,3-b]pyridin-1-yl)-
thieno[3,2-c]pyridin-4(5H)-one (3ia). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ia (27 mg) in 61% yield. Physical state:
yellow crystalline solid, mp: 208−210 °C, Rf value: 0.57 (30%
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.36 (dd, J = 4.8,
1.2 Hz, 1H), 8.03 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (d, J = 5.2 Hz,
1H), 7.75−7.72 (m, 2H), 7.53−7.47 (m, 3H), 7.45−7.43 (m, 2H),
7.19−7.15 (m, 2H), 7.08 (t, J = 7.6 Hz, 2H), 6.73 (d, J = 3.6 Hz,
1H), 6.60 (d, J = 7.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3):
δ 157.2, 149.8, 146.9, 144.8, 135.7, 131.5, 130.9, 130.1, 129.8, 129.4,
129.3, 129.0, 128.8, 128.4, 127.6, 127.0, 126.0, 122.3, 121.5, 119.2,
117.7, 100.9, 99.0, 80.8. IR (KBr, cm−1): 2940, 2856, 2371, 1657,
1634, 1558. HRMS (ESI) m/z: [M
+
Na]+ Calcd for
C28H17N3NaOS: 466.0990. Found: 466.0984.
6-Fluoro-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ja). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ja (37 mg) in 81% yield. Physical state:
yellow solid, mp: 199−202 °C, Rf value: 0.40 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 8.54 (dd, J = 8.8, 5.6 Hz, 1H), 8.35
6-Nitro-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-
1-yl)isoquinolin-1(2H)-one (3na). The title compound was prepared
according to general procedure B. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 3na (34 mg) in 71% yield. Physical state: yellow solid,
1
mp: 229−232 °C, Rf value: 0.40 (30% EtOAc/hexane). H NMR
(400 MHz, CDCl3): δ 8.69 (d, J = 8.4 Hz, 1H), 8.35 (d, J = 4.4 Hz,
1H), 8.27 (td, J = 8.8, 2.0 Hz, 2H), 8.05 (d, J = 7.6 Hz, 1H), 7.61−
7.51 (m, 5H), 7.45 (d, J = 3.6 Hz, 1H), 7.19 (dd, J = 7.0, 5.2 Hz,
2H), 7.08 (t, J = 7.6 Hz, 2H), 6.76 (d, J = 4.0 Hz, 1H), 6.55 (d, J =
7.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.7, 151.2,
146.7, 144.9, 138.1, 134.2, 131.7, 131.5, 131.3, 131.0, 130.0, 129.9,
129.8, 129.3, 129.2, 129.1, 128.8, 128.5, 128.5, 124.5, 121.7, 121.0,
119.3, 118.0, 101.4, 100.5, 80.5. IR (KBr, cm−1): 2921, 2204, 1691,
(dd, J = 4.4, 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J
= 7.6 Hz, 1H), 7.53−7.49 (m, 4H), 7.44 (d, J = 3.6 Hz, 1H), 7.26−
7.22 (m, 1H), 7.18−7.15 (m, 2H), 7.08−7.02 (m, 3H), 6.73 (d, J =
4.0 Hz, 1H), 6.53 (d, J = 7.2 Hz, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 166.1 (d, JC−F = 252 Hz), 160.2, 146.9, 144.8, 139.6 (d,
JC−F = 10 Hz), 135.1, 132.5 (d, JC−F = 10 Hz), 131.5, 131.1, 129.9,
129.5, 128.9, 128.9, 128.8 (d, JC−F = 5 Hz), 128.4, 127.7, 124.5,
124.5, 122.9, 122.9, 121.3, 119.2, 117.7, 116.7 (d, JC−F = 24 Hz),
111.9 (d, JC−F = 24 Hz), 101.0, 99.4, 80.9. 19F NMR (376 MHz,
CDCl3): δ −103.6. IR (KBr, cm−1): 2922, 2863, 2210, 1685, 1646,
1589, 1526. HRMS (ESI) m/z: [M
+
Na]+ Calcd for
C30H18N4NaO3: 505.1277. Found: 505.1271.
1-Oxo-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-
1-yl)-1,2 dihydroisoquinoline-6-carbonitrile (3oa). The title com-
pound was prepared according to general procedure B. The crude
reaction mixture was purified by column chromatography using silica
gel (230−400 mesh) giving 3oa (31 mg) in 68% yield. Physical
state: light yellow solid, mp: 137−140 °C, Rf value: 0.34 (30%
1615, 1557. HRMS (ESI) m/z: [M
+
Na]+ Calcd for
C30H18FN3NaO: 478.1332. Found: 478.1326.
6-Chloro-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ka). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ka (35 mg) in 75% yield. Physical state:
crystalline brown solid, mp: 233−236 °C, Rf value: 0.46 (30%
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 8.4
Hz, 1H), 8.34 (dd, J = 4.8, 1.6 Hz, 1H), 8.04 (dd, J = 7.6, 1.2 Hz,
1H), 7.75−7.71 (m, 2H), 7.56−7.52 (m, 4H), 7.49−7.47 (m, 1H),
7.44 (d, J = 4.0 Hz, 1H), 7.20−7.17 (m, 2H), 7.08 (t, J = 8.0 Hz,
2H), 7.25 (d, J = 4.0 Hz, 1H), 6.53 (d, J = 8.0 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 159.8, 146.7, 144.9, 137.5, 134.3,
131.6, 131.5, 131.0, 130.9, 130.3, 130.0, 129.9, 129.7, 129.2, 129.1,
128.7, 128.6, 128.6, 128.5, 123.9, 121.0, 119.2, 118.2, 117.9, 117.2,
101.3, 100.4, 80.5. IR (KBr, cm−1): 2924, 2853, 2232, 2211, 1699,
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 8.4
Hz, 1H), 8.35 (dd, J = 4.8, 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.2 Hz,
1H), 7.59−7.48 (m, 6H), 7.44 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 1.6
Hz, 1H), 7.16 (dd, J = 8.0, 5.6 Hz, 2H), 7.06 (t, J = 8.0 Hz, 2H),
6.73 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 8.0 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 160.3, 146.9, 144.9, 140.4, 138.4, 134.9,
131.6, 131.6, 131.1, 131.0, 129.9, 129.5, 129.0, 128.8, 128.8, 128.7,
128.4, 127.8, 125.8, 124.7, 124.3, 121.3, 119.2, 117.8, 101.0, 99.5,
80.9. IR (KBr, cm−1): 2932, 2848, 2208, 1678, 1594, 1542. HRMS
(ESI) m/z: [M + H]+ Calcd for C30H19ClN3O: 472.1217. Found:
472.1211.
1694, 1652. HRMS (ESI) m/z: [M
+
Na]+ Calcd for
C31H18N4NaO: 485.1378. Found: 485.1372.
4-Phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-6-
(trifluoromethyl)isoquinolin-1(2H)-one (3pa). The title compound
was prepared according to general procedure B. The crude reaction
9437
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3pa (36 mg) in 72% yield. Physical state:
light-brown solid, mp: 237−240 °C, Rf value: 0.57 (30% EtOAc/
m/z: [M + Na]+ Calcd for C30H18FN3NaO: 478.1331. Found:
478.1319.
7-Chloro-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3sa). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3sa (33 mg) in 70% yield. Physical state:
light-brown solid, mp: 263−266 °C, Rf value: 0.40 (30% EtOAc/
1
hexane). H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 8.4 Hz, 1H),
8.35 (dd, J = 4.8, 1.2 Hz, 1H), 8.03 (dd, J = 8.0, 1.6 Hz, 1H), 7.75
(dd, J = 8.4, 1.6 Hz, 1H), 7.67 (s, 1H), 7.60−7.51 (m, 5H), 7.45 (d,
J = 4.0 Hz, 1H), 7.20−7.16 (m, 2H), 7.07 (t, J = 7.6 Hz, 2H), 6.75
(d, J = 4.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H). 13C{1H} NMR (100
1
MHz, CDCl3): δ 160.1, 147.9, 146.8, 144.9, 137.3, 135.2 (q, JC−F
=
hexane). H NMR (700 MHz, CDCl3): δ 8.49 (d, J = 2.1 Hz, 1H),
32.0 Hz), 134.6, 131.6, 131.6, 131.1, 130.3, 129.9, 129.6, 129.1,
129.0, 128.9, 128.7, 128.6, 128.4, 128.0, 124.7, 124.7, 124.2 (q, JC−F
= 3.0 Hz), 123.8 (q, JC−F = 271.0 Hz), 123.5 (q, JC−F = 3.0 Hz),
101.2, 99.9, 80.7. 19F NMR (376 MHz, CDCl3): δ −63.0. IR (KBr,
cm−1): 2924, 2212, 1694, 1651, 1597, 1556. HRMS (ESI) m/z: [M
+ Na]+ Calcd for C31H18F3N3NaO: 528.1300. Found: 528.1294.
7-Methyl-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3qa). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3qa (37 mg) in 81% yield. Physical state:
brown solid, mp: 258−261 °C, Rf value: 0.50 (30% EtOAc/hexane).
1H NMR (700 MHz, CDCl3): δ 8.35 (d, J = 4.9 Hz, 1H), 8.33 (s,
1H), 8.02 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 7.0 Hz, 1H), 7.51−7.48
(m, 3H), 7.47−7.45 (m, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.16−7.12
(m, 2H), 7.04 (t, J = 7.7 Hz, 2H), 6.72 (d, J = 3.5 Hz, 1H), 6.52
(d, J = 7.7 Hz, 2H), 2.49 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 160.9, 146.8, 144.7, 138.8, 135.7, 134.9, 134.6, 131.6,
131.3, 131.2, 129.8, 129.1, 129.0, 128.9, 128.6, 128.5, 128.4, 128.3,
126.4, 126.3, 125.5, 125.4, 121.6, 119.2, 117.6, 100.8, 98.3, 81.2,
21.7. IR (KBr, cm−1): 3054, 2930, 2858, 2212, 1872, 1675, 1590.
HRMS (ESI) m/z: [M + Na]+ Calcd for C31H21N3NaO: 474.1582.
Found: 474.1583.
8.35 (d, J = 4.2 Hz, 1H), 8.03 (dd, J = 7.7, 1.4 Hz, 1H), 7.58 (dd, J
= 8.4, 2.1 Hz, 2H), 7.53−7.47 (m, 4H), 7.44 (d, J = 3.5 Hz, 1H),
7.35 (d, J = 8.4 Hz, 1H), 7.17−7.15 (m, 2H), 7.06 (t, J = 7.7 Hz,
2H), 6.73 (d, J = 3.5 Hz, 1H), 6.53 (d, J = 7.0 Hz, 2H). 13C{1H}
NMR (176 MHz, CDCl3): δ 159.9, 146.8, 144.8, 135.4, 135.2,
134.6, 133.9, 131.6, 131.5, 131.1, 129.9, 129.4, 128.9, 128.84,
128.80, 128.7, 128.6, 128.4, 128.1, 127.5, 126.7, 124.7, 121.4, 119.2,
117.8, 101.0, 99.2, 80.9. IR (KBr, cm−1): 3063, 2922, 2853, 2212,
1643, 1534. HRMS (ESI) m/z: [M + H]+ Calcd for C30H19ClN3O:
472.1211. Found: 472.1199.
7-Nitro-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-
1-yl)isoquinolin-1(2H)-one (3ta). The title compound was prepared
according to general procedure B. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 3ta (32 mg) in 67% yield. Physical state: yellow solid,
1
mp: 272−274 °C, Rf value: 0.50 (40% EtOAc/hexane). H NMR
(700 MHz, CDCl3): δ 9.34 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 8.4,
2.1 Hz, 1H), 8.35 (d, J = 4.2 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H),
7.59−7.49 (m, 6H), 7.46 (d, J = 4.2 Hz, 1H), 7.21−7.18 (m, 2H),
7.09 (t, J = 7.7 Hz, 2H), 6.76 (d, J = 3.5 Hz, 1H), 6.54 (d, J = 7.7
Hz, 2H). 13C{1H} NMR (176 MHz, CDCl3): δ 159.8, 146.79,
146.72, 144.9, 141.5, 134.6, 131.8, 131.5, 131.1, 130.2, 130.09,
130.01, 129.19, 129.16, 129.0, 128.57, 128.54, 127.9, 127.4, 126.6,
125.4, 124.1, 120.9, 119.2, 118.0, 101.5, 101.4, 80.7. IR (KBr,
cm−1): 3068, 2924, 1689, 1638, 1553, 1513. HRMS (ESI) m/z: [M
+ H]+ Calcd for C30H19N4O3: 483.1452. Found: 483.1443.
7-Fluoro-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ra). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ra (9 mg) in 20% yield. Physical state: off-
whitee solid, mp: 242−245 °C, Rf value: 0.60 (30% EtOAc/hexane).
1H NMR (700 MHz, CDCl3): δ 8.36 (dd, J = 4.9, 1.4 Hz, 1H), 8.18
4-Phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-7-
(trifluoromethyl)isoquinolin-1(2H)-one (3ua). The title compound
was prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ua (36 mg) in 71% yield. Physical state:
yellow solid, mp: 197−200 °C, Rf value: 0.53 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 8.34 (dd, J = 4.4, 1.2
(dd, J = 9.1, 2.8 Hz, 1H), 8.03 (dd, J = 7.7, 1.4 Hz, 1H), 7.59 (d, J
= 7.7 Hz, 1H), 7.54−7.47 (m, 4H), 7.45 (d, J = 4.2 Hz, 1H), 7.43−
7.41 (m, 1H), 7.37 (td, J = 8.4, 2.8 Hz, 1H), 7.18−7.13 (m, 2H),
7.06 (d, J = 7.7 Hz, 2H), 6.73 (d, J = 4.2 Hz, 1H), 6.52 (d, J = 7.7
Hz, 1H), 8.03 (dd, J = 8.0, 1.2 Hz, 1H), 7.82 (dd, J = 8.4, 1.6 Hz,
1H), 7.60−7.49 (m, 6H), 7.45 (d, J = 3.6 Hz, 1H), 7.19−7.16 (m,
2H), 7.07 (t, J = 7.6 Hz, 2H), 6.74 (d, J = 3.6 Hz, 1H), 6.54 (d, J =
8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.2, 146.8,
144.9, 139.5, 134.9, 131.6, 131.6, 131.5, 131.1, 130.2, 129.9, 129.9,
129.7, 129.6, 128.9 (q, JC−F = 6.0 Hz), 128.8, 128.7 (q, JC−F = 7.0
Hz), 128.4, 127.3, 126.8 (q, JC−F = 4.0 Hz), 126.4 (q, JC−F = 271.0
Hz), 126.3, 121.1, 119.2, 117.9, 101.2, 100.2, 80.7. 19F NMR (376
MHz, CDCl3): δ −62.5. IR (KBr, cm−1): 2935, 2848, 2210, 1691,
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.4 (d, JC−F
=
250 Hz), 160.1 (d, JC−F = 3 Hz), 146.8, 144.8, 135.4, 133.7 (d, JC−F
= 3 Hz), 131.6, 131.4, 131.1, 129.9, 129.3, 129.1 (d, JC−F = 8 Hz),
128.8, 128.77, 128.73, 128.4, 128.2 (d, JC−F = 8 Hz), 125.8 (d, JC−F
= 3 Hz), 124.8 (d, JC−F = 1 Hz), 122.2, 122.0, 121.5, 119.2, 117.8,
114.6 (d, JC−F = 23 Hz), 101.0, 98.8, 80.9. 19F NMR (376 MHz,
CDCl3): δ −110.7. IR (KBr, cm−1): 3051, 2982, 2848, 2263, 1687,
1633, 1562. HRMS (ESI) m/z: [M
+
Na]+ Calcd for
C30H18FN3NaO: 478.1331. Found: 478.1319.
1621, 1547. HRMS (ESI) m/z: [M
C31H18F3N3NaO: 528.1300. Found: 528.1294.
+
Na]+ Calcd for
5-Fluoro-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ra′). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ra’ (28 mg) in 61% yield. Physical state:
off-white solid, mp: 186−188 °C, Rf value: 0.45 (30% EtOAc/
8-Methyl-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3va). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3va (23 mg) in 52% yield. Physical state:
light-brown solid, mp: 144−147 °C, Rf value: 0.50 (30% EtOAc/
1
hexane). H NMR (700 MHz, CDCl3): δ 8.37 (d, J = 8.4 Hz, 1H),
7.35 (dd, J = 4.9, 1.4 Hz, 1H), 8.02 (dd, J = 7.7, 0.7 Hz, 1H),
7.57−7.56 (m, 1H), 7.51−7.43 (m, 6H), 7.33−7.29 (m, 1H), 7.16−
7.13 (m, 2H), 7.04 (t, J = 8.4 Hz, 2H), 6.72 (d, J = 3.5 Hz, 1H),
6.47 (d, J = 7.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
159.9 (d, JC−F = 3 Hz), 158.4 (d, JC−F = 256 Hz), 146.8, 144.8,
137.9 (d, JC−F = 4 Hz), 131.5, 130.6 (d, JC−F = 3 Hz), 130.1 (d,
JC−F = 3 Hz), 129.8, 129.5, 129.4, 129.2 (d, JC−F = 8 Hz), 128.8,
128.3, 128.1, 128.09, 128.02, 125.8 (d, JC−F = 9 Hz), 125.4 (d, JC−F
= 4 Hz), 121.37, 121.30 (d, JC−F = 2 Hz), 120.9, 120.7, 119.2,
117.8, 101.0, 99.9, 80.8. 19F NMR (376 MHz, CDCl3): δ −106.8.
IR (KBr, cm−1): 2980, 2925, 2213, 1667, 1603, 1524. HRMS (ESI)
1
hexane). H NMR (400 MHz, CDCl3): δ 8.37 (dd, J = 4.8, 1.2 Hz,
1H), 8.02 (dd, J = 8.0, 1.6 Hz, 1H), 7.57−7.40 (m, 8H), 7.31 (d, J
= 7.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.17−7.12 (m, 2H), 7.05
(t, J = 7.6 Hz, 2H), 6.72 (d, J = 4.0 Hz, 1H), 6.50 (d, J = 7.2 Hz,
2H), 2.91 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.5,
146.8, 144.7, 143.6, 138.8, 136.3, 132.7, 131.79, 131.71, 131.5,
131.3, 129.9, 129.22, 129.20, 128.7, 128.6, 128.4, 128.3, 126.3,
125.4, 125.0, 124.8, 121.7, 119.3, 117.6, 100.7, 98.5, 81.2, 24.3.IR
(KBr, cm−1): 2927, 2858, 2209, 1681, 1595. HRMS (ESI) m/z: [M
+ H]+ Calcd for C31H22N3O: 452.1757. Found: 452.1758.
9438
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
8-Fluoro-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3wa). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3wa (30 mg) in 67% yield. Physical state:
brown solid, mp: 173−176 °C, Rf value: 0.40 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 4.8 Hz, 1H), 8.02 (d, J
= 7.6 Hz, 1H), 7.59−7.48 (m, 6H), 7.44 (d, J = 4.0 Hz, 1H), 7.21−
7.15 (m, 4H), 7.06 (t, J = 7.6 Hz, 2H), 6.72 (d, J = 3.6 Hz, 1H),
6.52 (d, J = 7.6 Hz, 2H). 13C{1H} NMR (176 MHz, CDCl3): δ
163.3 (d, JC−F = 267.6 Hz), 157.7 (d, JC−F = 5.28 Hz), 146.9, 144.8,
139.7, 135.6, 134.5 (d, JC−F = 8.8 Hz), 131.68, 131.60, 131.2, 129.8,
4-(4-Methoxyphenyl)-3-((4-methoxyphenyl)ethynyl)-2-(1H-
pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3ae). The title
compound was prepared according to general procedure B. The
crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 3ae (40 mg) in 80% yield.
Physical state: yellowish-brown solid, mp: 172−175 °C, Rf value:
1
0.40 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.52
(d, J = 7.6 Hz, 1H), 8.35 (d, J = 3.6 Hz, 1H), 8.02 (dd, J = 8.0, 1.2
Hz, 1H), 7.64 (td, J = 7.8, 1.2 Hz, 1H), 7.55−7.50 (m, 2H), 7.45−
7.42 (m, 3H), 7.15 (dd, J = 7.6, 4.4 Hz, 1H), 7.05−7.02 (m, 2H),
6.71 (d, J = 4.0 Hz, 1H), 6.60 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.8
Hz, 2H) 3.89 (s, 3H), 3.21 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 161.0, 160.4, 159.7, 146.9, 144.7, 137.4, 133.5, 133.1,
132.9, 132.4, 129.7, 129.2, 129.1, 128.0, 127.8, 126.7, 126.4, 126.2,
124.2, 119.2, 117.6, 114.1, 114.0, 113.7, 100.7, 98.9, 80.2, 55.7, 55.5.
IR (KBr, cm−1): 2967, 2848, 2204, 1682, 1643, 1548. HRMS (ESI)
m/z: [M + H]+ Calcd for C32H24N3O3: 498.1818. Found: 498.1804.
4-(4-Fluorophenyl)-3-((4-fluorophenyl)ethynyl)-2-(1H-pyrrolo-
[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3af). The title com-
pound was prepared according to general procedure B. The crude
reaction mixture was purified by column chromatography using silica
gel (230−400 mesh) giving 3af (36 mg) in 77% yield. Physical
state: yellowish-orange solid, mp: 189−192 °C, Rf value: 0.40 (30%
129.4, 129.0, 128.9, 128.73, 128.72, 128.4, 127.6, 124.4 (d, JC−F
=
1.7 Hz), 122.5 (d, JC−F = 3.5 Hz), 121.3, 119.3, 117.7, 115.4 (d,
JC−F = 22.9 Hz), 115.3 (d, JC−F = 5.2 Hz), 101.0, 99.4, 80.9. 19F
NMR (376 MHz, CDCl3): δ −108.1. IR (KBr, cm−1): 2925, 2854,
2210, 1691, 1607, 1551. HRMS (ESI) m/z: [M + H]+ Calcd for
C30H19FN3O: 456.1507. Found: 456.1517.
2-(1H-Pyrrolo[2,3-b]pyridin-1-yl)-4-(p-tolyl)-3-(p-tolylethynyl)-
isoquinolin-1(2H)-one (3ab). The title compound was prepared
according to general procedure B. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 3ab (38 mg) in 82% yield. Physical state: light-yellow
solid, mp: 190−194 °C, Rf value: 0.42 (30% EtOAc/hexane). 1H
NMR (400 MHz, CDCl3): δ 8.52 (dd, J = 8.0, 0.8 Hz, 1H), 8.34
(dd, J = 4.4, 1.2 Hz, 1H), 8.00 (dd, J = 7.8, 1.2 Hz, 1H), 7.62 (td, J
= 7.7, 1.0 Hz, 1H), 7.55−7.39 (m, 5H), 7.30 (d, J = 8.2 Hz, 2H),
7.14 (dd, J = 7.8, 4.7 Hz, 1H), 6.87 (d, J = 7.9 Hz, 2H), 6.70 (d, J
= 3.8 Hz, 1H), 6.45 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H), 2.21 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 160.9, 146.9, 144.7, 139.6,
138.2, 137.2, 133.4, 132.5, 131.5, 131.4, 131.1, 129.7, 129.3, 129.2,
129.1, 129.1, 129.0, 128.1, 126.4, 126.4, 126.3, 125.0, 119.2, 118.6,
117.6, 100.7, 98.9, 80.7, 21.8, 21.7. IR (KBr, cm−1): 2919, 2208,
1685, 1634, 1514. HRMS (ESI) m/z: [M + H]+ Calcd for
C32H24N3O: 466.1919. Found: 466.1913.
2-(1H-Pyrrolo[2,3-b]pyridin-1-yl)-4-(m-tolyl)-3-(m-tolylethynyl)-
isoquinolin-1(2H)-one (3ac). The title compound was prepared
according to general procedure B. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 3ac (37 mg) in 80% yield. Physical state: orange-
yellow solid, mp: 189−192 °C, Rf value: 0.40 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 8.0 Hz, 1H), 8.36 (s,
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.53 (dd, J = 7.6,
0.8 Hz, 1H), 8.35 (dd, J = 4.8, 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.6
Hz, 1H), 7.66 (td, J = 7.8, 1.2 Hz, 1H), 7.58−7.54 (m, 2H), 7.51−
7.47 (m, 1H), 7.44 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H),
7.24−7.19 (m, 2H), 7.16 (dd, J = 7.6, 4.8 Hz, 1H), 6.78 (t, J = 8.8
Hz, 2H), 6.72 (d, J = 4.0 Hz, 1H), 6.53−6.50 (m, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 163.1 (d, JC−F = 250.0 Hz), 163.0 (d,
JC−F = 246.0 Hz), 160.8, 146.9, 144.8, 143.3, 136.9, 133.7, 133.5 (d,
JC−F = 9.0 Hz), 133.0 (d, JC−F = 8.0 Hz), 131.4 (d, JC−F = 3.0 Hz),
129.8, 129.3, 128.9, 128.5, 126.5, 126.4, 126.2, 124.1, 119.2, 117.7,
117.5 (d, JC−F = 3.0 Hz), 116.3, 115.9 (d, JC−F = 22.0 Hz), 115.8
(d, JC−F = 21.0 Hz), 115.6, 101.3, 100.9, 97.8, 80.7. 19F NMR (376
MHz, CDCl3): δ −108.6, −113.1. IR (KBr, cm−1): 2967, 2851,
2210, 1682, 1601, 1550, 1510. HRMS (ESI) m/z: calcd for [M +
Na]+ C30H17F2N3NaO: 496.1237; found 496.1231.
4-Butyl-3-(hex-1-yn-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-
isoquinolin-1(2H)-one (3ag). The title compound was prepared
according to general procedure B. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 3ag (29 mg) in 73% yield. Physical state: yellow oil, Rf
1H), 8.02 (dd, J = 7.8, 1.1 Hz, 1H), 7.63 (td, J = 7.6, 1.2 Hz, 1H),
7.54 (t, J = 7.2 Hz, 1H), 7.45−7.38 (m, 4H), 7.34−7.27 (m, 2H),
7.15 (dd, J = 7.8, 4.7 Hz, 1H), 6.96−6.93 (m, 2H), 6.72 (d, J = 3.8
Hz, 1H), 6.36 (d, J = 5.7 Hz, 1H), 6.30 (s, 1H), 2.43 (d, J = 10.0
Hz, 3H), 2.14 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.9,
146.9, 144.7, 138.3, 138.0, 137.1, 135.4, 133.5, 132.2, 132.1, 131.8,
130.1, 129.7, 129.2, 129.2, 129.1, 129.0, 128.7, 128.6, 128.5, 128.4,
128.2, 126.5, 126.4, 125.4, 121.4, 119.3, 117.6, 100.8, 99.0, 81.0,
21.8, 21.3. IR (KBr, cm−1): 3055, 2922, 2209, 1682, 1604, 1579.
HRMS (ESI) m/z: [M + H]+ Calcd for C32H24N3O: 466.1919.
Found: 466.1902.
1
value: 0.48 (30% EtOAc/hexane). H NMR (400 MHz, CDCl3): δ
8.46 (d, J = 8.0 Hz, 1H), 8.32 (dd, J = 4.8, 1.2 Hz, 1H), 7.95 (dd, J
= 7.6, 1.2 Hz, 1H), 7.76−7.71 (m, 2H), 7.53−7.49 (m, 1H), 7.31
(d, J = 3.6 Hz, 1H), 7.12 (dd, J = 7.6, 4.8 Hz, 1H), 6.63 (d, J = 4.0
Hz, 1H), 3.00−2.88 (m, 2H), 2.03 (t, J = 6.0 Hz, 2H), 1.73−1.62
(m, 2H), 1.53−1.44 (m, 2H), 1.08−0.91 (m, 7H), 0.68 (t, J = 7.2
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.1, 146.9, 144.6,
136.5, 133.5, 129.6, 129.4, 129.0, 127.7, 126.5, 125.8, 124.1, 122.6,
119.3, 117.4, 100.9, 100.5, 72.0, 32.1, 30.1, 29.6, 23.2, 21.7, 19.2,
14.2, 13.7. IR (KBr, cm−1): 2957, 2928, 2227, 1683, 1594, 1553.
HRMS (ESI) m/z: [M + Na]+ Calcd for C26H27N3NaO: 420.2052.
Found: 420.2047.
4-(4-(tert-Butyl)phenyl)-3-((4-(tert-butyl)phenyl)ethynyl)-2-(1H-
pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3ad). The title
compound was prepared according to general procedure B. The
crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 3ad (44 mg) in 81% yield.
Physical state: brown solid, mp: 102−105 °C, Rf value: 0.52 (30%
3-(Hept-1-yn-1-yl)-4-pentyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-
isoquinolin-1(2H)-one (3ah). The title compound was prepared
according to general procedure B. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 3ah (30 mg) in 70% yield. Physical state: yellow solid,
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 8.0
1
mp: 84−86 °C, Rf value: 0.54 (30% EtOAc/hexane). H NMR (400
Hz, 1H), 8.34 (dd, J = 4.8, 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.6 Hz,
1H), 7.64 (td, J = 7.6, 1.2 Hz, 1H), 7.55−7.42 (m, 7H), 7.15 (dd, J
= 8.0, 4.8 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 4.0 Hz,
1H), 6.45 (d, J = 8.4 Hz, 2H), 1.41 (s, 9H), 1.19 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3): δ 161.0, 152.7, 151.4, 146.9, 144.7,
137.2, 133.5, 132.6, 131.4, 131.2, 130.9, 129.7, 129.2, 129.0, 128.1,
126.6, 126.5, 126.3, 125.5, 125.3, 125.3, 119.2, 118.7, 117.6, 100.8,
98.9, 80.9, 35.0, 31.7, 31.3. IR (KBr, cm−1): 2961, 2867, 2209, 1686,
1602, 1549. HRMS (ESI) m/z: [M + H]+ Calcd for C38H36N3O:
550.2858. Found: 550.2852.
MHz, CDCl3): δ 8.46 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 4.4 Hz, 1H),
7.95 (d, J = 7.4 Hz, 1H), 7.76−7.70 (m, 2H), 7.50 (td, J = 7.2, 1.6
Hz, 1H), 7.32 (d, J = 4.0 Hz, 1H), 7.12 (dd, J = 7.6, 4.4 Hz, 1H),
6.63 (d, J = 4.0 Hz, 1H), 2.99−2.90 (m, 2H), 2.01 (t, J = 6.4 Hz,
2H), 1.74−1.60 (m, 2H), 1.48−1.33 (m, 4H), 1.04−1.01 (m, 4H),
0.98−0.87 (m, 5H), 0.78 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 161.1, 146.8, 144.5, 136.5, 133.5, 129.6, 129.4,
129.0, 127.7, 126.5, 125.8, 124.0, 122.7, 119.3, 117.4, 101.0, 100.5,
71.9, 32.3, 30.8, 29.8, 29.6, 27.7, 22.7, 22.3, 19.5, 14.3, 14.1. IR
9439
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(KBr, cm−1): 2955, 2929, 2858, 2227, 1682, 1605, 1553. HRMS
(ESI) m/z: [M + Na]+ Calcd for C28H31N3NaO: 448.2365. Found:
448.2359.
146.9, 146.4, 144.7, 140.1, 137.4, 135.5, 131.7, 131.4, 131.2, 129.88,
129.83, 129.2, 129.0, 128.8, 128.69, 128.66, 128.63, 128.3, 127.8,
127.4, 125.5, 125.2, 124.6, 121.5, 119.2, 117.6, 100.8, 98.8, 81.2. IR
(KBr, cm−1): 3062, 2943, 2822, 2224, 1687, 1592, 1546. HRMS
(ESI) m/z: [M + H]+ Calcd for C36H24N3O: 514.1914. Found:
514.1887.
4-Phenethyl-3-(4-phenylbut-1-yn-1-yl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ai). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3ai (34 mg) in 68% yield. Physical state:
viscous oil, Rf value: 0.40 (30% EtOAc/hexane). 1H NMR (400
MHz, CDCl3): δ 8.49 (d, J = 8.0 Hz, 1H), 8.34 (dd, J = 4.8, 1.2 Hz,
1H), 7.96 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (d, J = 3.6 Hz, 2H), 7.56−
7.50 (m, 1H), 7.31−7.24 (m, 3H), 7.22−7.12 (m, 7H), 6.94 (d, J =
7.2 Hz, 2H), 6.63 (d, J = 3.6 Hz, 1H), 3.17 (t, J = 8.4 Hz, 2H),
2.96−2.84 (m, 2H), 2.36−2.22 (m, 4H). 13C{1H} NMR (100 MHz,
CDCl3): δ 161.0, 146.9, 144.6, 141.6, 140.1, 136.2, 133.7, 129.7,
129.6, 129.0, 128.7, 128.7, 128.4, 127.9, 126.7, 126.6, 126.4, 126.1,
125.3, 123.8, 121.7, 119.2, 117.5, 101.1, 100.6, 100.3, 72.3, 36.0,
34.3, 31.9, 21.6. IR (KBr, cm−1): 2925, 2228, 1681, 1605, 1553.
HRMS (ESI) m/z: [M + Na]+ Calcd for C34H27N3NaO: 516.2052.
Found: 516.2046.
4-Phenyl-3,6-bis(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-
yl)isoquinolin-1(2H)-one (7). The title compound was prepared
according to general procedure B. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 7 (54 mg) in 82% yield. Physical state: yellow solid,
1
mp: 194−197 °C, Rf value: 0.50 (30% EtOAc/hexane). H NMR
(400 MHz, CDCl3): δ 8.50 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 4.0 Hz,
1H), 8.03 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.62 (d, J
= 7.2 Hz, 1H), 7.54−7.52 (m, 7H), 7.46 (d, J = 3.6 Hz, 1H), 7.35−
7.33 (m, 3H), 7.16 (t, J = 8.0 Hz, 2H), 7.06 (t, J = 7.6 Hz, 2H),
6.73 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 7.6 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 160.4, 146.8, 144.8, 137.0, 135.2, 132.1,
131.7, 131.5, 131.2, 131.1, 129.8, 129.39, 129.34, 129.2, 129.1,
128.93, 128.90, 128.8, 128.7, 128.3, 127.1, 125.5, 124.8, 122.7,
121.4, 119.2, 117.7, 100.9, 99.1, 93.2, 88.9, 81.0. IR (KBr, cm−1):
3036, 2958, 2923, 2208, 2183, 1634, 1598, 1554. HRMS (ESI) m/z:
[M + H]+ Calcd for C38H24N3O: 538.1914. Found: 538.1890.
4-Phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-6-
((trimethylsilyl)ethynyl)isoquinolin-1(2H)-one (9). The title com-
pound was prepared according to general procedure F. The crude
reaction mixture was purified by column chromatography using silica
gel (230−400 mesh) giving 9 (43 mg) in 80% yield. Physical state:
yellow brown solid, mp: 254−256 °C, Rf value: 0.40 (20% EtOAc/
4-Cyclopropyl-3-(cyclopropylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3aj). The title compound was
prepared according to general procedure B. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 3aj (31 mg) in 84% yield. Physical state:
yellow crystalline solid, mp: 176−178 °C, Rf value: 0.42 (30%
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.0
Hz, 1H), 8.32 (d, J = 4.0 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.97
(dd, J = 7.6, 1.2 Hz, 1H), 7.74 (td, J = 8.4, 1.2 Hz, 1H), 7.50 (t, J =
7.2 Hz 1H), 7.27 (t, J = 4.0 Hz 1H), 7.14 (dd, J = 7.6, 4.8 Hz, 1H),
6.63 (d, J = 4.0 Hz, 1H), 1.90−1.83 (m, 1H), 1.12−1.02 (m, 3H),
0.89−0.80 (m, 2H), 0.60−0.50 (m, 2H), 0.17−0.12 (m, 1H), −0.04
- −0.09 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.2,
146.6, 144.4, 138.2, 133.3, 129.7, 129.0, 129.0, 127.9, 127.6, 125.9,
124.8, 121.9, 119.1, 117.4, 105.8, 100.4, 66.9, 10.6, 9.0, 8.9, 8.4, 8.4,
0.2. IR (KBr, cm−1): 3008, 2923, 2223, 1679, 1593, 1554. HRMS
(ESI) m/z: [M + Na]+ Calcd for C24H19N3NaO: 388.1426. Found:
388.1420.
1
hexane). H NMR (400 MHz, CDCl3): δ 8.45 (d, J = 8.4 Hz, 1H),
8.36 (dd, J = 4.8, 1.2 Hz, 1H), 8.02 (dd, J = 7.6, 1.2 Hz, 1H), 7.60
(dd, J = 8.0, 1.2 Hz, 2H), 7.53−7.51 (m, 4H), 7.47 (d, J = 1.2 Hz,
1H), 7.44 (d, J = 3.6 Hz, 1H), 7.17−7.14 (m, 2H), 7.06 (t, J = 7.6
Hz, 2H), 6.73 (d, J = 4.0 Hz, 1H), 6.51 (d, J = 7.2 Hz, 2H), 0.24
(s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.4, 146.8, 144.8,
136.9, 135.2, 131.7, 131.59, 131.53, 131.3, 129.9, 129.46, 129.40,
129.2, 128.8, 128.7, 128.5, 128.4, 127.1, 125.7, 124.8, 121.4, 119.2,
117.7, 104.2, 101.0, 99.1, 98.8, 80.9, 0.1. IR (KBr, cm−1): 2956,
2929, 2828, 2211, 2155, 1688, 1584, 1533. HRMS (ESI) m/z: [M +
H]+ Calcd for C35H28N3O: 534.1996. Found: 534.1981.
6-Ethynyl-4-phenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (10). The title compound was
prepared according to general procedure G. The crude reaction
mixture was purified by column chromatography using silica gel
(230−400 mesh) giving 10 (43 mg) in 94% yield. Physical state:
white solid, mp: 252−254 °C, Rf value: 0.45 (30% EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.0 Hz, 1H), 8.36 (d, J
= 4.4 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.8 Hz, 1H),
7.53−7.49 (m, 5H), 7.45 (d, J = 3.6 Hz, 1H), 7.16 (t, J = 7.6 Hz,
2H), 7.06 (t, J = 7.6 Hz, 2H), 6.73 (d, J = 3.6 Hz, 1H), 6.52 (d, J =
7.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.4, 146.9,
144.8, 137.0, 135.1, 131.7, 131.5, 131.3, 131.2, 130.0, 129.8, 129.4,
129.3, 128.9, 128.78, 128.76, 128.4, 127.5, 127.3, 126.1, 124.6,
121.4, 119.3, 117.7, 101.0, 99.3, 83.0, 81.0, 80.9. IR (KBr, cm−1):
2957, 2930, 2856, 2216, 2192, 1686, 1606, 1565, 1504. HRMS
(ESI) m/z: [M + H]+ Calcd for C32H20N3O: 462.1601. Found:
462.1579.
3-((4-Methoxyphenyl)ethynyl)-4-phenyl-2-(1H-pyrrolo[2,3-b]-
pyridin-1-yl)isoquinolin-1(2H)-one (3ak) and 4-(4-Methoxyphen-
yl)-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-
1(2H)-one (3ak′) (1:1). The title compound was prepared according
to general procedure B. The crude reaction mixture was purified by
column chromatography using silica gel (230−400 mesh) giving 3ak
and 3ak’ (37 mg) in 79% yield. Physical state: yellow crystalline
1
solid, Rf -value: 0.40 (40% EtOAc/hexane). H NMR (400 MHz,
CDCl3): δ 8.52 (d, J = 8.0 Hz, 2H), 8.36 (d, J = 4.0 Hz, 2H), 8.02
(td, J = 7.6, 1.6 Hz, 2H), 7.66−7.43 (m, 14H), 7.39 (d, J = 8.4 Hz,
1H), 7.17−7.14 (m, 3H), 7.09−7.03 (m, 4H), 6.71 (t, J = 3.6 Hz
2H), 6.59−6.56 (m, 4H), 6.46 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H),
3.69 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.0, 160.9,
160.4, 159.8, 146.9, 144.7, 137.3, 137.1, 135.7, 133.5, 133.1, 132,9,
132.4, 131.7, 131.5, 131.3, 129.8, 129.7, 129.2, 129.1, 129.0, 128.7,
128.5, 128.4, 128.38, 128.30, 128.1, 127.6, 126.7, 126.5, 126.4,
126.37, 126.33, 126.2, 125.5, 125.0, 124.6, 121.6, 119.27, 119.25,
117.67, 117.64, 114.14, 114.11, 114.0, 113.6, 100.8, 100.7, 99.1,
98.5, 81.3, 80.1, 55.7, 55.5. IR (KBr, cm−1): 3016, 2928, 2856, 2221,
1677, 1596, 1555, 1326, 1248. HRMS (ESI) m/z: [M + H]+ Calcd
for C31H22N3O2: 468.1674. Found: 468.1707.
6,6′-(Ethyne-1,2-diyl)bis(4-phenyl-3-(phenylethynyl)-2-(1H-
pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one) (11). The title
compound was prepared according to general procedure H. The
crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 11 (70 mg) in 78% yield.
Physical state: white solid, mp: > 300 °C, Rf value: 0.50 (50%
4,6-Diphenyl-3-(phenylethynyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-
yl)isoquinolin-1(2H)-one (5). The title compound was prepared
according to general procedure B. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 5 (48 mg) in 93% yield. Physical state: yellow solid,
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 8.4
1
mp: 238−240 °C, Rf value: 0.50 (30% EtOAc/hexane). H NMR
Hz, 2H), 8.36 (dd, J = 4.8, 1.2 Hz, 2H), 8.03 (dd, J = 7.6, 1.2 Hz,
2H), 7.66 (dd, J = 8.4, 1.6 Hz, 2H), 7.61 (d, J = 7.2 Hz, 2H), 7.55−
7.51 (m, 10H), 7.45 (d, J = 4.0 Hz, 2H), 7.16 (t, J = 7.2 Hz, 4H),
7.06 (t, J = 7.6 Hz, 4H), 6.73 (d, J = 7.2 Hz, 2H), 6.52 (d, J = 7.2
Hz, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.4, 146.9, 144.8,
137.1, 135.1, 131.7, 131.5, 131.2, 131.1, 129.9, 129.4, 128.98,
(400 MHz, CDCl3): δ 8.52 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 4.4 Hz,
1H), 7.94 (d, J = 7.2 Hz, 1H), 7.70 (dd, J = 8.4, 1.2 Hz, 1H), 7.56
(d, J = 6.8 Hz, 1H), 7.51 (s, 1H), 7.46−7.29 (m, 10H), 7.09−7.05
(m, 2H), 6.98 (t, J = 7.6 Hz, 2H), 6.65 (d, J = 3.6 Hz, 1H), 6.45
(d, J = 7.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.8,
9440
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
128.91, 128.8, 128.4, 127.9, 127.4, 126.0, 124.7, 121.4, 119.2, 117.7,
101.0, 99.3, 92.1, 81.0. IR (KBr, cm−1): 3033, 2944, 2922, 2217,
2163, 1683, 1582, 1542. HRMS (ESI) m/z: [M + H]+ Calcd for
C62H37N6O2: 897.2973. Found: 897.2919.
Prateep Singh Sagara − School of Basic Sciences, Indian
Institute of Technology Mandi, Kamand, Himachal Pradesh
175005, India
Asit Ghosh − School of Chemical Sciences, National Institute
of Science Education and Research (NISER), HBNI, Jatani,
Odisha 752050, India
Gopal Krushna Das Adhikari − School of Chemical Sciences,
National Institute of Science Education and Research
(NISER), HBNI, Jatani, Odisha 752050, India
3-Phenethyl-4-phenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-
isoquinolin-1(2H)-one (12). The title compound was prepared
according to general procedure I. The crude reaction mixture was
purified by column chromatography using silica gel (230−400
mesh) giving 12 (44 mg) in 80% yield. Physical state: white solid,
1
mp: 196−198 °C, Rf value: 0.40 (20% EtOAc/hexane). H NMR
(400 MHz, CDCl3): δ 8.42 (d, J = 8.0 Hz, 1H), 8.35 (dd, J = 4.4,
0.8 Hz, 1H), 8.03 (dd, J = 8.0, 1.6 Hz, 1H), 7.56−7.43 (m, 6H),
7.35−7.33 (m, 2H), 7.19 (dd, J = 7.6, 4.8 Hz, 1H), 7.07 (d, J = 8.0
Hz, 1H), 7.02−7.00 (m, 3H), 6.76 (d, J = 4.0 Hz, 1H), 6.39 (dd, J
= 5.6, 2.0 Hz, 2H), 2.66−2.61 (m, 2H), 2.56−2.51 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 161.9, 147.7, 144.9, 141.7,
140.8, 138.3, 136.5, 133.4, 131.4, 131.1, 130.1, 129.9, 129.3, 129.1,
128.7, 128.6, 128.3, 128.2, 127.0, 126.3, 125.9, 125.1, 119.6, 118.9,
118.0, 101.7, 36.2, 33.2. IR (KBr, cm−1): 3068, 2934, 2844, 1683,
1618, 1590, 1553, 1486, 736, 694. HRMS (ESI) m/z: [M + H]+
Calcd for C30H24N3O: 442.1914. Found: 442.1899.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00759
Author Contributions
§B.V.P. and P.S.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
4-Phenyl-3-(phenylethynyl)isoquinolin-1(2H)-one (13). The title
compound was prepared according to general procedure J. The
crude reaction mixture was purified by column chromatography
using silica gel (230−400 mesh) giving 13 (23 mg) in 72% yield.
Physical state: colorless solid, mp: 229−232 °C, Rf value: 0.45 (40%
We are thankful to NISER, Department of Atomic Energy
(DAE), and IIT Mandi for facilities. We acknowledge the
Council for Scientific and Industrial Research (CSIR), New
Delhi (Grant 02(0256)/16/EMR II) and the Science and
Engineering Research Board (SERB), New Delhi (Grant
EMRII/2017/001475) for financial support. P.S.S. thanks
University Grants Commission, Government of India. B.V.P.
thanks DST-INSPIRE, and A.G. thanks DAE. G.K.D.A.
thanks CSIR for a research fellowship. We are also thankful
to Suneel Kumar and Puneet Sood, IIT Mandi, for
instrumental help.
1
EtOAc/hexane). H NMR (400 MHz, CDCl3): δ 9.53 (s, 1H), 8.50
(dd, J = 8.0, 1.2 Hz, 1H), 7.60 (td, J = 7.2, 1.6 Hz, 1H), 7.54−7.45
(m, 5H), 7.39 (d, J = 7.6 Hz, 1H), 7.31−7.23 (m, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 162.6, 137.9, 135.7, 133.0, 131.9,
131.4, 129.5, 129.2, 128.9, 128.7, 128.6, 128.4, 128.0, 127.7, 126.2,
124.5, 121.9, 121.0, 96.3, 83.4. IR (KBr, cm−1): 3484, 3056, 2922,
2853, 1689, 1645, 1547. HRMS (ESI) m/z: [M + Na]+ Calcd for
C23H15NNaO: 344.1501. Found: 344.1036.
ABBREVIATIONS
TFE Trifluoroethanol
EtOAc Ethyl acetate
DCM Dichloromethane
DMF Dimethylformamide
DCE 1,2-Dichloroethane
HOBt Hydroxybenzotriazole
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00759.
■
sı
X-ray crystallographic analysis of 3aa, 3fa, and 3aj
(PDF)
FAIR data, including the primary NMR FID files, for
compounds 1g, 1p, 1r−1w, 3aa−3wa, 3ab−3ak, 5, 7,
and 9−13 (ZIP)
REFERENCES
■
(1) (a) Asano, Y.; Kitamura, S.; Ohra, T.; Itoh, F.; Kajino, M.;
Tamura, T.; Kaneko, M.; Ikeda, S.; Igata, H.; Kawamoto, T.; et al.
Discovery, synthesis and biological evaluation of isoquinolones as
novel and highly selective JNK inhibitors (2). Bioorg. Med. Chem.
2008, 16, 4699−4714. (b) Upadhyay, N. S.; Thorat, V. H.; Sato, R.;
Annamalai, P.; Chuang, S.-C.; Cheng, C.-H. Synthesis of
Isoquinolones via RhCatalyzed C-H Activation of Substituted
Benzamides using Air as the Sole Oxidant in Water. Green Chem.
2017, 19, 3219−3224. (c) Kong, R.; Tan, J.; Ma, X.; Chen, W.;
Wang, C. X. Prediction of the binding mode between BMS-378806
and HIV-1 gp120 by docking and molecular dynamics simulation.
Biochim. Biophys. Acta, Proteins Proteomics 2006, 1764, 766−772.
(d) Lee, J. X.; Loh, K.; Yap, Y. PI3K/Akt/MTOR Inhibitors in
Breast Cancer. Cancer Biol. Med. 2015, 12, 342−354.
(2) For selected recent reviews on transition metal catalyzed C−H
activation, see (a) Wencel-Delord, J.; Glorius, F. C-H Bond
Activation Enables the Rapid Construction and Late-Stage
Diversification of Functional Molecules. Nat. Chem. 2013, 5, 369−
375. (b) Rouquet, G.; Chatani, N. Catalytic Functionalization of
C(sp2)-H and C(sp3)-H Bonds by Using Bidentate Directing
Groups. Angew. Chem., Int. Ed. 2013, 52, 11726−11743.
(c) Thirunavukkarasu, V. S.; Kozhushkov, S. I.; Ackermann, L. C-
H Nitrogenation and Oxygenation by Ruthenium Catalysis. Chem.
Commun. 2014, 50, 29−39. (d) Moselage, M.; Li, J.; Ackermann, L.
Cobalt-Catalyzed C-H Activation. ACS Catal. 2016, 6, 498−525.
Accession Codes
CCDC 1963789, 1963791, and 1963792 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Author
Ponneri Chandrababu Ravikumar − School of Chemical
Sciences, National Institute of Science Education and
Research (NISER), HBNI, Jatani, Odisha 752050, India;
orcid.org/0000-0002-5264-820X; Email: pcr@
niser.ac.in
■
Authors
Bedadyuti Vedvyas Pati − School of Chemical Sciences,
National Institute of Science Education and Research
(NISER), HBNI, Jatani, Odisha 752050, India
9441
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(e) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. TransitionMetal-
Catalyzed C-H Bond Addition to Carbonyls, Imines, and Related
Polarized π Bonds. Chem. Rev. 2017, 117, 9163−9227. (f) Sambiagio,
C.; Schönbauer, D.; Blieck, R.; DaoHuy, T.; Pototschnig, G.; Schaaf,
P.; Wiesinger, T.; Zia, M. F.; WencelDelord, J.; Besset, T.; Maes, B.
Oxidative Annulation of Nitrogen-Containing Arenes with Alkynes:
An Atom-Economical Route to Heterocyclic Quaternary Ammonium
Salts. Angew. Chem., Int. Ed. 2016, 55, 1844−1848. (d) Qiu, Y.;
Tian, C.; Massignan, L.; Rogge, T.; Ackermann, L. Electrooxidative
Ruthenium-Catalyzed C-H/O-H Annulation by Weak O-Coordina-
tion. Angew. Chem., Int. Ed. 2018, 57, 5818−5822. (e) Xu, X.; Zhao,
H.; Xu, J.; Chen, C.; Pan, Y.; Luo, Z.; Zhang, Z.; Li, H.; Xu, L.
Rhodium(III)-Catalyzed Oxidative Annulation of 2,2′ -Bipyridine N-
Oxides with Alkynes via Dual C-H Bond Activation. Org. Lett. 2018,
20, 3843−3847. (f) Liu, J.; Fang, H.; Cheng, R.; Wang, Z.; Yang, Y.;
You, J. Cascade intramolecular imidoylation and C-H activation/
annulation of benzimidoyl chlorides with alkynes: one-pot synthesis
of 7H-dibenzo[de, h]quinoline analogues. Chem. Commun. 2019, 55,
7097−7100.
(7) (a) Zhang, W.; Li, H.; Wang, L. Cobalt-Catalyzed Temper-
ature-Dependent Annulation of 3- Aryl- 1,2,4-oxadiazolones with
1,3-Diynes: An Approach to p Conjugated Molecules. Adv. Synth.
Catal. 2019, 361, 2885−2896. (b) Yu, D.-G.; De Azambuja, F.;
Gensch, T.; Daniliuc, C. G.; Glorius, F. The C-H Activation/1,3-
Diyne Strategy: Highly Selective Direct Synthesis of Diverse
Bisheterocycles by Rh(III) Catalysis. Angew. Chem., Int. Ed. 2014,
53, 9650−9654. (c) Kathiravan, S.; Nicholls, I. A. Cobalt Catalyzed,
Regioselective C(sp2)-H Activation of Amides with 1,3-Diynes. Org.
Lett. 2017, 19, 4758−4761. (d) Sen, M.; Mandal, R.; Das, A.; Kalsi,
D.; Sundararaju, B. Cp*CoIII-Catalyzed Bis-isoquinolone Synthesis
by C-H Annulation of Arylamide with 1,3-Diyne. Chem. - Eur. J.
2017, 23, 17454−17457. (e) Gao, Y.; Zeng, F.; Sun, X.; Zeng, M.;
Yang, Z.; Huang, X.; Shen, G.; Tan, Y.; Feng, R.; Qi, C. One-pot
Synthesis of Alkynylated Coumarins via Rhodium-Catalyzed
Annulation of Aryl Thiocarbamates with 1,3-Diynes or Terminal
Alkynes. Adv. Synth. Catal. 2018, 360, 1328−1333. (f) Martinez, A.
M.; Alonso, I.; Rodriguez, N.; Gomez Arrayas, R.; Carretero, J. C.
Rhodium-Catalyzed Copper-Assisted Intermolecular Domino C-H
Annulation of 1,3-Diynes with Picolinamides: Access to Pentacyclic
π-Extended Systems. Chem. - Eur. J. 2019, 25, 5733−5742. (g) Feng,
R.; Ning, H.; Su, H.; Gao, Y.; Yin, H.; Wang, Y.; Yang, Z.; Qi, C.
Selective Synthesis of Alkynylated Isoquinolines and Biisoquinolines
via Rh(III) Catalyzed C-H Activation/1,3-Diyne Strategy. J. Org.
Chem. 2017, 82, 10408−10417. (h) Mei, R.; Ma, W.; Zhang, Y.;
Guo, X.; Ackermann, L. Cobaltaelectro-Catalyzed Oxidative C-H/N-
H Activation with 1,3-Diynes by Electro-Removable Hydrazides.
Org. Lett. 2019, 21, 6534−6538. (i) Qian, S.; Pu, X.; Chang, G.;
Huang, Y.; Yang, Y. Rh(III)-Catalysed oxidative C-H activation/
domino annulation of anilines with 1,3-diynes:A rapid access to blue
emitting tricyclic N,O-heteroaromatics. Org. Lett. 2020, 22, 5309−
5313. and references cited therein.
(8) (a) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.;
Chatani, N. Highly Regioselective Carbonylation of Unactivated
C(sp3)-H Bonds by Ruthenium Carbonyl. J. Am. Chem. Soc. 2011,
133, 8070−8073. (b) Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.;
Zhang, Q.; Zhang, S.-Q.; Shi, B.-F. Pd(II)-Catalyzed Alkoxylation of
Unactivated C(sp3)-H and C(sp2)-H Bonds Using a Removable
Directing Group: Efficient Synthesis of Alkyl Ethers Shi. Chem. Sci.
2013, 4, 4187−4192. (c) Li, X.; Liu, Y.-H.; Gu, W.-J.; Li, B.; Chen,
F.-J.; Shi, B.-F. Copper-Mediated Hydroxylation of Arenes and
Heteroarenes Directed by a Removable Bidentate Auxiliary. Org.
Lett. 2014, 16, 3904−3907. (d) Ackermann, L. Carboxylate-Assisted
Ruthenium-Catalyzed Alkyne Annulations by C-H/Het-H Bond
Functionalizations. Acc. Chem. Res. 2014, 47, 281−295. (e) Shang,
M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. Cu(II)-Mediated C-H
Amidation and Amination of Arenes: Exceptional Compatibility
with Heterocycles. J. Am. Chem. Soc. 2014, 136, 3354−3357.
(f) Hao, X.-Q.; Chen, L.-J.; Ren, B.; Li, L.-Y.; Yang, X.-Y.; Gong, J.-
F.; Niu, J.-L.; Song, M.-P. Copper-Mediated Direct Aryloxylation of
Benzamides Assisted by an N, O-Bidentate Directing Group. Org.
Lett. 2014, 16, 1104−1107. (g) Zhang, Q.; Yin, X.-S.; Chen, K.;
Zhang, S.-Q.; Shi, B.-F. Stereoselective Synthesis of Chiral β-Fluoro
α-Amino Acids via Pd(II)- Catalyzed Fluorination of Unactivated
Methylene C(sp3)-H Bonds: Scope and Mechanistic Studies. J. Am.
U. W.; Schnu
applied in metal-catalysed C-H functionalisation chemistry. Chem.
ller, T.; Zell,
̈
rch, M. A comprehensive overview of directing groups
Soc. Rev. 2018, 47, 6603−6743. (g) Gandeepan, P.; Mu
̈
D.; Cera, G.; Warratz, S.; Ackermann, L. 3d Transition Metals for
C-H Activation. Chem. Rev. 2019, 119, 2192−2452. and references
cited therein.
(3) (a) Wang, D.- H.; Wasa, M.; Giri, R.; Yu, J.-Q. Pd(II)-
Catalyzed Cross-Coupling of sp3 C-H Bonds with sp2 and sp3
Boronic Acids Using Air as the Oxidant. J. Am. Chem. Soc. 2008,
130, 7190−7191. (b) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-
Q. A Simple and Versa-tile Amide Directing Group for C-H
Functionalizations. Angew. Chem., Int. Ed. 2016, 55, 10578−10599.
(c) Das, R.; Kumar, G. S.; Kapur, M. Amides as Weak Coordinating
Groups in Proximal C-H Bond Acti-vation. Eur. J. Org. Chem. 2017,
2017, 5439−5459.
(4) (a) Yu, X.; Chen, K.; Guo, S.; Shi, P.; Song, C.; Zhu, J. Direct
Access to Cobaltacycles via C-H Activation: N-Chloroamide-
Enabled Room-Temperature Synthesis of Heterocycles. Org. Lett.
2017, 19, 5348−5351. (b) Upadhyay, N. S.; Thorat, V. H.; Sato, R.;
Annamalai, P.; Chuang, S.-C.; Cheng, C.-H. Synthesis of
isoquinolones via Rh-catalyzed C-H activation of substituted
benzamides using air as the sole oxidant in water. Green Chem.
2017, 19, 3219−3224. (c) Yedage, S. L.; Bhanage, B. M. Ru(ii)/
PEG-400 as a highly efficient and recyclable catalytic media for
annulation and olefination reactions via C-H bond activation. Green
Chem. 2016, 18, 5635−5642. (d) Sivakumar, G.; Vijeta, A.;
Jeganmohan, M. Cobalt-Catalyzed Cyclization of N-Methoxy
Benzamides with Alkynes using an Internal Oxidant through C-H/
N-O Bond Activation. Chem. - Eur. J. 2016, 22, 5899−5903.
(e) Ackermann, L.; Lygin, A. V.; Hofmann, N. Ruthenium-Catalyzed
Oxidative Annulation by Cleavage of C-H/N-H Bonds. Angew.
Chem., Int. Ed. 2011, 50, 6379−6382. (f) Li, B.; Feng, H.; Xu, S.;
Wang, B. Ruthenium-Catalyzed Isoquinolone Synthesis through CH
Activation Using an Oxidizing Directing Group. Chem. - Eur. J.
2011, 17, 12573−12577. (g) Song, G.; Chen, D.; Pan, C.-L.;
Crabtree, R. H.; Li, X. Rh-Catalyzed Oxidative Coupling between
Primary and Secondary Benzamides and Alkynes: Synthesis of
Polycyclic Amides. J. Org. Chem. 2010, 75, 7487−7490.
(5) For selected reviews, see (a) Satoh, T.; Miura, M. Oxidative
coupling of aromatic substrates with alkynes and alkenes under
rhodium catalysis. Chem. - Eur. J. 2010, 16, 11212−11222. (b) Song,
G.; Wang, F.; Li, X. C-C, C-O and C-N bond formation via
rhodium(iii)-catalyzed oxidative C-H activation. Chem. Soc. Rev.
2012, 41, 3651−3678. (c) Ackermann, L. Carboxylate-Assisted
Ruthenium-Catalyzed Alkyne Annulations by C-H/Het-H Bond
Functionalizations. Acc. Chem. Res. 2014, 47, 281−295. (d) Yang, Y.;
Li, K.; Cheng, Y.; Wan, D.; Li, M.; You, J. Rhodium-catalyzed
annulation of arenes with alkynes through weak chelation-assisted C-
H activation. Chem. Commun. 2016, 52, 2872−2884. (e) Gulías, M.;
Mascarenas, J. L. Metal-Catalyzed Annulations through Activation
̃
and Cleavage of C-H Bonds. Angew. Chem., Int. Ed. 2016, 55,
11000−11019. (f) Duarah, G.; Kaishap, P. P.; Begum, T.; Gogoi, S.
Recent Advances in Ruthenium(II)-Catalyzed C-H Bond Activation
and Alkyne Annulation Reactions. Adv. Synth. Catal. 2019, 361,
654−672. and references cited therein.
(6) For selected examples, see (a) Zhang, G.; Yang, L.; Wang, Y.;
Xie, Y.; Huang, H. An Efficient Rh/O2 Catalytic System for
Oxidative C-H Activation/Annulation: Evidence for Rh(I) to
Rh(III) Oxidation by Molecular Oxygen. J. Am. Chem. Soc. 2013,
135, 8850−8853. (b) Warratz, S.; Kornhaaβ, C.; Cajaraville, A.;
Niepötter, B.; Stalke, D.; Ackermann, L. Ruthenium(II)-Catalyzed
C-H Activation/Alkyne Annulation by Weak Coordination with O2
as the Sole Oxidant. Angew. Chem., Int. Ed. 2015, 54, 5513−5517.
(c) Prakash, S.; Muralirajan, K.; Cheng, C.-H. Cobalt-Catalyzed
9442
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Chem. Soc. 2015, 137, 8219−8226. (h) Odom, A. L.; McDaniel, T.
J. Titanium-Catalyzed Multicomponent Couplings: Efficient One-
Pot Syntheses of Nitrogen Heterocycles. Acc. Chem. Res. 2015, 48,
2822−2833. (i) Liu, T.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q.
Palladium(II)- Catalyzed Site-Selective C(sp3)-H Alkynylation of
Oligopeptides: A Linch-pin Approach for Oligopeptide-Drug
Conjugation. Angew. Chem., Int. Ed. 2017, 56, 10924−10927. and
references cited therein.
Catalysis for Selective Heterocoupling of Terminal Alkynes. J. Am.
Chem. Soc. 2016, 138, 12348−12351.
(14) (a) Simmons, E. M.; Hartwig, J. F. On the Interpretation of
Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations
by Transition-Metal Complexes. Angew. Chem., Int. Ed. 2012, 51,
3066−3072. (b) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. Proton Abstraction Mechanism for the Palladium-
Catalyzed Intramolecular Arylation. J. Am. Chem. Soc. 2006, 128,
1066−1067. (c) Tan, E.; Quinonero, O.; Elena de Orbe, M.;
Echavarren, A. M. Broad-Scope Rh-Catalyzed Inverse-Sonogashira
Reaction Directed by Weakly Coordinating Groups. ACS Catal.
(9) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly
Regioselective Arylation of sp3 C-H Bonds Catalyzed by Palladium
Acetate. J. Am. Chem. Soc. 2005, 127, 13154−13155. (b) Daugulis,
O.; Do, H.-Q.; Shabashov, D. Palladium- and Copper-Catalyzed
Arylation of Carbon-Hydrogen Bonds. Acc. Chem. Res. 2009, 42,
1074−1086. (c) Shabashov, D.; Daugulis, O. Auxiliary-Assisted
Palladium-Catalyzed Arylation and Alkylation of sp2 and sp3
Carbon-Hydrogen Bonds. J. Am. Chem. Soc. 2010, 132, 3965−
3972. (d) Ano, Y.; Tobisu, M.; Chatani, N. Palladium-Catalyzed
Direct Ethynylation of C(sp3)-H Bonds in Aliphatic Carboxylic Acid
Derivatives. J. Am. Chem. Soc. 2011, 133, 12984−12986. (e) Asako,
S.; Ilies, L.; Nakamura, E. Iron-Catalyzed Ortho Allylation of
Aromatic Carboxamides with Allyl Ethers. J. Am. Chem. Soc. 2013,
135, 17755−17757. (f) Grigorjeva, L.; Daugulis, O. Cobalt-
Catalyzed, AminoquinolineDirected sp2 C-H Bond Alkenylation by
Alkynes. Angew. Chem., Int. Ed. 2014, 53, 10209−10212.
(g) Grigorjeva, L.; Daugulis, O. Cobalt-Catalyzed, Aminoquinoline-
Directed Coupling of sp2 C-H Bonds with Alkenes. Org. Lett. 2014,
16, 4684−4687. (h) Grigorjeva, L.; Daugulis, O. Cobalt-Catalyzed
Direct Carbonylation of Aminoquinoline Benzamides. Org. Lett.
2014, 16, 4688−4690. (i) Matsubara, T.; Asako, S.; Ilies, L.;
Nakamura, E. Synthesis of Anthranilic Acid Derivatives through
Iron-Catalyzed Ortho Amination of Aromatic Carboxamides with N-
Chloroamines. J. Am. Chem. Soc. 2014, 136, 646−649. (j) Nguyen,
T. T.; Grigorjeva, L.; Daugulis, O. Cobalt-Catalyzed, Aminoquino-
line-Directed Functionalization of Phosphinic Amide sp2 C-H
Bonds. ACS Catal. 2016, 6, 551−554.
2018, 8, 2166−2172. (d) Zell, D.; Bursch, M.; Muller, V.; Grimme,
̈
S.; Ackermann, L. Full Selectivity Control in Cobalt (III)-Catalyzed
C-H Alkylations by Switching of the C-H Activation Mechanism.
Angew. Chem., Int. Ed. 2017, 56, 10378−10382; Angew. Chem. 2017,
129, 10514−10518. (e) Ma, W.; Mei, R.; Tenti, G.; Ackermann, L.
Ruthenium(II)- Catalyzed Oxidative C-H Alkenylations of Sulfonic
Acids, Sulfonyl Chlorides and Sulfonamides. Chem. - Eur. J. 2014,
20, 15248−15251.
(15) Pati, B. V.; Ghosh, A.; Ravikumar, P. C. Rhodium-Catalyzed
Room Temperature C-C Activation of Cyclopropanol for One-Step
Access to Diverse 1,6- Diketones. Org. Lett. 2020, 22, 2854−2860.
NOTE ADDED AFTER ASAP PUBLICATION
Scheme 3 was replaced on June 29, 2021.
■
(10) (a) Li, F.; Song, Q.; Yang, L.; Wu, G.; Zhang, X. Supra-
Amphiphiles Formed by Complexation of Azulene-Based Amphi-
philes and Pyrene in Aqueous Solution: from Cylindrical Micelles to
Disklike Nanosheets. Chem. Commun. 2013, 49, 1808. (b) Shoji, T.;
Maruyama, M.; Tanaka, M.; Nagai, E.; Shimomura, E.; Fujimori, K.;
Ito, S.; Okujima, T.; Toyota, M.; Yasunami, M. Synthesis and
Properties of (3-Phenyl-1-azulenyl)tetracyanobetadienes and Tris-
(aryltetracyanobetadiene)s Connected with 1,3,5-Tri(1-azulenyl)-
benzene Core. ChemistrySelect 2016, 1, 49−57. (c) Xu, S.;
Adamski, M.; Killer, M.; Schibli, E. M.; Frisken, B. J.; Holdcroft,
S. Sulfo-phenylated polyphenylenes containing sterically hindered
pyridines. Macromolecules 2019, 52, 2548−2559. (d) Arakawa, Y.;
Kang, S.; Nakajima, S.; Sakajiri, K.; Cho, Y.; Kawauchi, S.;
Watanabe, J.; Konishi, G. Diphenyltriacetylenes: Novel Nematic
Liquid Crystal Materials and Analysis of their Nematic Phase-
Transition and Birefringence Behaviours. J. Mater. Chem. C 2013, 1,
8094−8102.
(11) (a) Sagara, P. S.; Siril, P. F.; Ravikumar, P. C. N-Amino-7-
azaindole as the N,N′-Bidentate Directing Group: Ruthenium-
Catalyzed Oxidative Annulation of N-(7-Azaindole)benzamides with
Alkynes via C-H Bond Activation. J. Org. Chem. 2019, 84, 12314−
12323. (b) Pati, B. V.; Sagara, P. S.; Ghosh, A.; Mohanty, S. R.;
Ravikumar, P. C. Ruthenium-Catalyzed Cross Dehydrogenative
Annulation Of N-(7-Azaindole)benzamides with Maleimides: One-
Step Access to Highly Functionalized Pyrroloisoquinoline. J. Org.
Chem. 2021, 86 (9), 6551−6565.
(12) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. NMR chemical
shifts of common laboratory solvents as trace impurities. J. Org.
Chem. 1997, 62, 7512−7515.
(13) (a) Singha, R.; Nandi, S.; Ray, J. K. Bromine-mediated
cyclization of 1,4-diaryl buta-1,3-diyne to 1,2,3-tribromo-4-aryl
naphthalene. Tetrahedron Lett. 2012, 53, 6531−6534. (b) Su, L.;
Dong, J.; Liu, L.; Sun, M.; Qiu, R.; Zhou, Y.; Yin, S.-F. Copper
9443
https://doi.org/10.1021/acs.joc.1c00759
J. Org. Chem. 2021, 86, 9428−9443