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

Article abstract of DOI:10.1021/acs.joc.9b01598

We report a new application of N-amino-7-azaindole as a new bidentate-directing group for [Ru(p-cymene)Cl₂]₂-catalyzed C(sp²)-H alkenylation/annulation of N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamides with internal alkynes to afford N-isoquinolono-7-azaindole via the formation of C-C and C-N bonds. The reaction shows a wide range of substrate scope with different symmetrical and unsymmetrical alkynes, affording the desired product in good to excellent yields. In the case of unsymmetrical alkynes, a highly regioselective product was obtained, which was confirmed by single-crystal X-ray crystallography. A new ruthenium-4-methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide complex was isolated, and its structure was confirmed by single-crystal X-ray crystallography.

Full text of DOI:10.1021/acs.joc.9b01598

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Article
N-Amino-7-Azaindole as N,N’- Bidentate Directing Group:
Ruthenium-Catalyzed Oxidative Annulation of N-(7-
Azaindole) Benzamides with Alkynes via C-H Bond Activation
Prateep Singh Sagara, Prem Felix Siril, and Ponneri Chandrababu Ravikumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01598 • Publication Date (Web): 11 Sep 2019
Downloaded from pubs.acs.org on September 12, 2019
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N-Amino-7-Azaindole as N,N’- Bidentate Directing Group:
Ruthenium-Catalyzed Oxidative Annulation of N-(7-Azaindole)
Benzamides with Alkynes via C-H Bond Activation
Prateep Singh Sagara,† Prem Felix Siril,† Ponneri Chandrababu Ravikumar*‡
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†School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh-
175005, India.
‡School of Chemical Sciences, National Institute of Science Education and Research
(NISER) Bhubaneswar, Jatani Campus, Odisha 752050, India.
O
O
H
N
Ru
N
N
N
Ar
Ar
H
N
Ph
Ph
N
Ph
Ph
25 examples
Up to 85% yield
ABSTRACT: We report a new application of N-amino-7-azaindole as a new bidentate directing group for [Ru(p-
cymene)Cl2]2-catalyzed C(sp2)-H alkenylation/annulation of N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamides with
internal alkynes to afford N-isoquinolono-7-azaindole via the formation of C-C and C-N bond. The reaction shows
a wide range of substrate scope with different symmetrical and unsymmetrical alkynes affording the desired
product in good to excellent yields. In the case of unsymmetrical alkynes a highly regioselective product was
obtained, which was confirmed by single crystal X-ray Crystallography. A new ruthenium-4-methyl-N-(1H-
pyrrolo[2,3-b]pyridin-1-yl)benzamide complex was isolated and its structure was confirmed by single crystal X-ray
Crystallography.
INTRODUCTION
Directing group assisted transition-metal-catalysed C-H activation and annulation reaction has been utilized
for the synthesis of numerous biologically important molecular scaffolds such as isoquinolines,1
isoquinolones, 2 pyridines,3 and indoles4 etc. Ever since the discovery of 8-aminoquinoline as a directing group
for C-H activation reactions by Dauglis et al. in the year 2005,5 it has become the most successful and widely
used directing group for C-H activation reactions.6 The rigidity of its structure, ionic and hemilabile neutral
nitrogen binding modes are just the right combination required for C-H activation reactions. One major
draw-back on the use of this directing group for C-H/N-H annulation type of reaction is that isoquinoline
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unit cannot be removed from the substrate easily from the reaction due to the presence of strong C-N bond,7
this reduces its scope for further modification of the products. The 5-methoxy-8-aminoquinolines were
demonstrated to solve this problem, however it is very rarely used.8 There are several reports for C-H
activation reactions utilizing N-O bond containing directing group which would also act as an internal
oxidant.9 However, the N-N bond containing directing groups are not well explored for C-H activation.
Therefore, we started a new program in our group to discover new N-N bond containing directing groups for
C-H activation reaction wherein directing group could be easily cleaved for further synthetic modification of
the product. We designed and developed N-amino-7-azaindole as a new substitute for 8-aminoquinoline,
wherein the azaindole unit can be removed easily after the reaction using hydrazine. To the best of our
knowledge, this is the first report of N-N bond cleavage using hydrazine. The procedure is very simple and
mild as compared to the methods reported in the literature.10 The details of this new N-N bond cleavage
process is explained in the later part of this article. Although C-H alkenylation/annulation reaction is well
documented in the literature.11 It is worth mentioning that N-amino-7-azaindole derivatives as N,N’-bidentate
directing group were not explored in previous reports. Moreover, the bidentate auxiliary containing N-N bond
linkage seems to be rare and helpful for easy removal as compared to the C-N counterpart (Scheme 1).12
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Scheme 1. Overview of this work
(a) Previous work: Various bidentate direction groups for isoquinolone synthesis.11a, b, 12b
O
O
DG
DG
[M]
N
N
H
R1
R2
R2
R1
N
DG's :
Reported
N
N
N
Our work:
(b)
Ru(II)-catalyzed annulation of alkyne via C-H activation.
O
O
N
N
[Ru]
N
N
N
H
R1
R2
N
R2
R1
RESULTS AND DISCUSSION
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+
N-amination of 7-azaindole can be easily performed using monochloramine as NH2 transfer reagent using the
procedure reported by Hynes et al.13 Since ruthenium (II) is known to activate ortho C(sp2)-H bond of benzamides,
we have taken N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (1a) as a model substrate for the annulation purpose.
For screening, we decided to use the commercially available [Ru(p-cymene)Cl2]2 catalyst for the synthesis of N-N
bonded isoquinolone derivatives of 7-azaindoles using diphenyl acetylene as coupling partner.14
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Table 1: Optimization of reaction conditionsa,b
O
O
N
N
[RuCl2(p-cymene)]2 (5 mol%)
N
N
H
N
N
1a
additive 1, additive 2
Solvent/Temp, 16h
Ph
3a
Ph
Ph
Ph
2a
entry
additive-1
additive-2
solvent/temp
(°C)
Yield b
30
(%)
1
2
3
4
-
NaOAc
CsOAc
KOAc
MeOH/100
MeOH/120
H2O /100
TFE/100
PivOH
30
50
60
MesCOOH
MesCOOH
KOAc
5
6
MesCOOH
MesCOOH
Cu(OAc)2.H2O
KOAc
TFE/100
65
15
PEG-400/100
7
8
MesCOOH
-
KOAc
CsOAc
DCE/120
DCE/120
DCE/120
DCE/120
DCE/120
DCE/120
45
40
25
50
28
34
9
AgSbF6
-
-
10
11c
12d
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
AgSbF6
AgSbF6
13e
14f
AgSbF6
AgSbF6
Cu(OAc)2.H2O
Cu(OAc)2.H2O
DCE/120
DCE/120
42
60
15g
16h
AgSbF6
-
Cu(OAc)2.H2O
DCE/120
85
-
DCE/120
trace
aReaction conditions: 1a (0.5 mmol), 2a (1.2 equiv), [Ru(p-cymene)Cl2]2 (5.0 mol %), Additive 1 (10
mol %), Additive 2 (2.0 equiv), solvent (3.0 mL), 100 – 120 °C, 16h. b Isolated Yield. Cu(OAc)2.H2O
c
(10mol%), dCu(OAc)2.H2O (30mol%), eCu(OAc)2.H2O (50mol%), fCu(OAc)2.H2O (100mol%),
g
Cu(OAc)2.H2O (200 mol%), h without additives.
By keeping the time constant we explored various acetates, acids, solvents at different temperatures (Table 1, entry
1-8), but the yields of 3a were not promising. It has been observed in the literature that silver salts such as AgSbF6
is known to improve the reaction yields. Therefore we decided to screen various combinations of AgSbF6 and
Cu(OAc)2.H2O as additives. When the reaction was performed only with AgSbF6 in 1,2 dichloroethane as solvent
we obtained 3a in 25% isolated yield (Table 1, entry 9). Similarly, in presence of only Cu(OAc)2.H2O, 3a was obtained
in 50% yield (Table 1, entry 10). Then, we decided to use both the additives together by changing the Cu(OAc)2.H2O
percentage gradually as following; 10 mol %, 30 mol %, 50 mol %, 100 mol % and 200 mol % affording the product
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yields 28%, 34%, 42%, 60%, and 85% respectively (Table 1, entry 11-15). It is very clear that by increasing the
equivalent amount of copper salt the product yield also gradually increased. These preliminary experiments
highlighted [RuCl2(p-cymene)]2 /AgSbF6/Cu(OAc)2.H2O (Table S1, entry 15) as the best catalyst system and DCE
was the most suitable among the solvents used. Herein, we demonstrate an efficient ruthenium-catalyzed
cyclization of N-(7-azaindole) benzamides 1a with alkynes 2a to give isoquinolones in very good yields. With the
optimized conditions in hand, we examined the scope of the alkynes with N-(1H-pyrrolo[2,3-b]pyridin-1-
yl)benzamide 1a, as shown in Scheme 2. Screening of symmetrically substituted diaryl alkynes having methoxy, t-
butyl and halogen groups at the para- position gave the products 3b–f in 73 – 82% yields. The use of terminal
alkynes gave no corresponding product. Whereas the symmetrical alkynes bearing aliphatic groups like 2-butyne,
3-hexyne, 4-octyne gave the corresponding product 3g–i in 62%–72% yields. Interestingly, when unsymmetrical
alkynes such as phenyl(alkyl)alkynes was used only one regioselective isomer was obtained. viz 1-phenyl-1-propyne
2j, and 1-phenyl-1-butyne 2k afforded the products in in good yields 60% & 68%. 3j and 3k respectively. The
regioselective product 3k was further confirmed by X-ray crystallography.
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Scheme 2. Substrate scope for the various alkynes a, b
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aReaction conditions: All reactions were performed with 1a
(0.5 mmol), 2 (0.75 mmol), [Ru(p-cymene)Cl2]2 (5.0 mol
%), AgSbF6 (10 mol %), and Cu(OAc)2·H2O (1.0 mmol) in
2.0 mL of DCE at 120 °C, 16 h in sealed tube. bisolated yields
We have also explored scope of various substituted N-(7-azaindole)benzamides (Scheme 3). The generality of the
annulation reactions were explored using benzamides containing various functional groups 4a-n with 2a under
optimized reaction conditions. The reactions are successful for both electron poor 4a–f and electron rich 4g–k
amides. Therefore, the substituted benzamides 4a–n with diphenylacetylene 2a behaved similarly to afford the
isoquinolones 5a–n in good yields 60%–70%. The reaction also worked well with 2-naphtahylamide affording the
product 5l 60% yield. Extension of the annulation process to heteroarylamide, 3-thiopheneamide worked smoothly
under catalytic conditions and gave the annulation product 5m, (71%) in a regioselective manner.
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Scheme 3. Substrate scope for the various benzamides a, b
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aAll reactions were performed with 4 (0.5 mmol), 2a (0.75 mmol),
[Ru]-catalyst (0.025 mmol), AgSbF6 (0.05 mmol), and
Cu(OAc)2·H2O (1.0 mmol) in 2.0 mL DCE at 120 °C, 16 h in sealed
tube. bisolated yields.
It is worth noticing that the C-H bond functionalization was occurred at the more active 2–position of the
thiophene. When we used a meta-substituted Benzamides 4n with diphenyacetylene 2a we got the product 5n as
a single regioisomer in which the less hindered C-H bond got activated. The utility of directing group has to be
tested for its easy removal, 8-aminoquinoline is a popular and very successful directing group employed in C-H
activation reactions, but removal of quinoline moiety from the cyclized product is not very easy. However, in the
case of N-amino-7-azaindole, it has the same directing group ability as 8-aminoquinoline but removal is very easy.
For instance, compound 3a when treated with N2H4.H2O in the presence of ethanol at room temperature for 2h,
yielded the corresponding amide 3aa13 in 80% yield through N-N bond cleavage (Scheme 4). The same condition
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was implemented for the cleavage of N-N bond of the other substituted 7-azaindole Isoquinolones 3g & 5k and
obtained the corresponding isoquinolones 3gg & 5kk in excellent yields (Scheme 4).
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Scheme 4. Directing group removal.
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entry
R
Alk/Ar
Ph
Yield (%)
80 (3aa)
79 (3gg)
82 (5kk)
1
H
2
3
H
CH3
Ph
SCH3
This methodology in itself is a newly discovered reaction and it was never reported before. As compared to
literature methods for the cleavage of N-N bonds, by far this is the most-simple approach for the cleavage of N-N
bonds. We also performed a stoichiometric reaction and isolated the intermediate ruthenium complex with the
substituted benzamide (Scheme 5). The complex-4j’ was obtained by treating the 4-methyl-N-(1H-pyrrolo[2,3-
b]pyridin-1yl)benzamide 4j with [Ru(p-cymene)Cl2]2 in 40% yield. In this complex, ruthenium is coordinated to the
4-methyl-N-(1H-pyr rolo[2,3-b]pyridin-1-yl)benzamide 4j moiety in a N,N fashion.
Scheme 5. Synthesis of the ruthenium complex – 4j’.
The structure of the complex-4j’ was further confirmed by X-ray crystallography (CCDC: 1913752). To have an
insight into the reaction mechanism, a few mechanistic study experiments were conducted (Scheme 6). In the
reaction 1a with D2O under the optimized condition using DCE as a solvent, the ortho- hydrogen of amide and C-
2 and C-3 hydrogens of 7-azaindole were deuterated and obtained deuterio-1a in 60% yield with 90%, 20%, and
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50% of deuterium incorporation respectively. Meanwhile, the intramolecular reaction involving 1a / [D5]-1a with
3
4
3-Hexyne showed the KIE value of 2.11, indicating that the C-H activating step might be turnover limiting step.
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7
8
9
Scheme 6. Preliminary mechanistic studies. a) Deuterium exchange and b) Kinetic isotopic effect.
(a)
20% D
O
50% D
O
N
N
[Ru(p-cymene)Cl2]2 (5 mol %)
N
H
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N
H
AgSbF6 (10 mol %)
Cu(OAc)2. H2O (2.0 equiv)
N
N
90% D
D2O,DCE, 120 °C, 16 h
1a
deuterio - 1a, 60%
(b)
O
N
N
H
O
N
(1.2 equiv)
[RuCl2(p-cymene)]2 (5 mol %)
N
N
1a,
0.5 mmol
H4/D4
N
AgSbF6(10 mol %)
Cu(OAc)2.H2O(2.0 equiv)
D
O
D
D
N
N
DCE, 120 °C, 30 min
3h
[D4/H4] -
H
N
D
D
KIE
2.11
=
= kH/kD
1a
[D5] - , 0.5 mmol
Based on the above mechanistic information and precedent reports15 a plausible mechanism is proposed (Scheme
7). Firstly, the AgSbF6 removes the chloro (Cl-) ligand form the Ruthenium complex in the presence of the
Cu(OAc)2.H2O and gives a cationic ruthenium acetate complex 6. Which in turn coordinate with the benzamide
1a forms a five membered ruthenacycle intermediate A. The coordinative insertion of diphenyl acetylene into the
Ru-carbon bond of the complex A gives the intermediate B. Finally, Reductive elimination of the intermediate B in
the presence of Copper salt gives the desired product C and finally active ruthenium complex 6 regenerates for the
next catalyst cycle.
Scheme 7. Proposed mechanism for the Ruthenium catalyzed Isoquinolone synthesis via bidentate
directing group
[RuCl2(p-cymene)]2
AgSbF6
Cu(OAc)2.2H2O
AgCl
O
N
O
N
N
N
[Ru(X)n(L)] [Y]n
H
N
N
6
X = SbF6, OAc
Ph
C
L = p-cymene
Ph
N
O
N
Cu(OAc)2.H2O
R
O
N
N
[X]n
N
Ru
L
Ru
N
L
Ph
[X]n
Ph
A
B
Ph
Ph
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CONCLUSIONS
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In summary, we have developed a novel and efficient ruthenium–catalysed ortho-C(sp2)-H functionalization and
alkenylation/annulation of benzamides with internal alkynes via a novel N-amino-7-azaindole- assisted C-H
activation. This protocol provides access to a series of N-isoquinolono-7-azaindole in good to excellent yields.
Moreover, the isoquinoline unit of 7-azaindole directing group can be further removed using hydrazine under mild
conditions, which is also a newly discovered reaction for N-N bond cleavage. The reaction features a high
regioselectivity and good substrate scope. A ruthenium 4-methyl-N-(2,3-b)pyrrolo[2,3-b]pyridin-1-yl)benzamide
complex was isolated and characterized, showing the key role played by the 7-Azaindole moiety. Further
applications of N-amino-7-azaindole as a bidentate directing group in the other types of C-H functionalization and
mechanistic details are currently being investigated in our laboratory.
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EXPERIMENTAL SECTION
All the chemical reagents were purchased from commercial suppliers and used without further purification.
Solvents were distilled and stored in the presence of 4 Å molecular sieves prior to use. Thin layer chromatography
was carried out on aluminum silica plates 60 F254, purchased from Merck. All the synthesized products were
purified by using column chromatography on 100-200 mesh silica. Melting points were determined on Stuart
SMP30 apparatus using an open capillary method with ramp rate of 5 °C min−1 and are uncorrected.
NMR spectra were recorded on a JEOL-USA (JNM-ECX500) spectrometer in CDCl3-d1 and DMSO-d6 taking TMS
(Tetramethyl Silane) as the internal standard (δ = 0). All 1H NMR spectra in CDCl3 or DMSO-d6 were recorded at
500 MHz frequency, and all 13C-NMR spectra were recorded at 125 MHz frequency. The coupling constants (J) are
reported in Hz and signal multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), quintet (qu),
doublet of doublets (dd), multiplet (m), or broad (br. s). FT-IR spectra were acquired on a PerkinElmer Spectrum
2 spectrometer. High-resolution mass spectra were recorded on an advance Bruker Daltonics (impact HD) UHR-
QqTOF (ultra-high resolution Qq time-of-flight) mass spectrometer.
The synthesis of N-amino -7-azaindole (b) was prepared according to the literature report.10
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Representative Procedures for the preparation of substrates.
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EDC.HCl (1.2 mmol) and N, N- Diisopropylethylamine (2.5 mmol) were added to a solution of aromatic carboxylic
acid (a) (1.0 mmol), N-amino-7-azaindole (b) (1.0 mmol) and HOBt (1.2 mmol) in dimethylformamide (3.0 mL) and
stirred for 12h at room temperature. After the completion, the reaction was diluted with EtOAc (2x30 mL) and then
washed with water (5.0 mL), brine solution (5 mL) and dried over Na2SO4 filtered and concentrated in vacuum.
The resulting residue was purified by column chromatography to give the pure benzamides.
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N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (1a). Yield: (213 mg, 90%) ; Off-white solid, Rf = 0.35 (Hex/EA = 2/1), mp:
(193–195) °C. 1H NMR (500 MHz, CDCl3) δ 12.33 (s, 1H), 8.28 (d, J = 4.1 Hz, 1H), 7.93 (dd, J = 1.4, 7.5 Hz, 1H), 7.91 (d,
J = 7.5 Hz, 2H), 7.41 (t, J = 6.8 Hz, 1H), 7.32 (d, J = 3.4 Hz, 1H), 7.27-7.24 (m, 2H), 7.11 (dd, J = 4.8, 7.6 Hz, 1H), 6.51 (d,
J = 3.4 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.8, 146.2, 141.9, 132.0, 130.6, 130.4, 130.2, 128.3, 127.6, 119.9, 116.7,
99.3. IR(ATR) cm-1: 3251, 3119, 2940, 1695, 1674, 1580, 1438, 1363, 1267, 1127, 892, 798, 715, 687. HRMS (ESI): calculated
for C14H12N3O [M + H]+: 238.0980, found 238.0977. It was crystallized from dichloromethane.
4-bromo-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4a). Yield: (289 mg, 92%) ; white solid, Rf = 0.4 (Hex/EA =
2/1), mp: (164 –166) °C. 1H NMR (500 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.25 (d, J = 4.8 Hz, 1H), 8.04 (d, J = 7.5 Hz,
1H), 7.96 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 3.4 Hz 1H), 7.17 (dd, J = 4.8 & 7.5 Hz, 1H), 6.57 (d, J
= 4.1 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 165.5, 146.3, 143.2, 131.9, 130.8, 130.4, 129.8, 129.1, 126.4, 118.6, 116.8,
98.7. IR (ATR) cm-1: 3494, 3436, 3180, 2918, 2849, 1668, 1591, 1561, 1484, 1272, 1140, 1069, 1008, 903, 845, 793, 715.
HRMS (ESI): calculated for C14H11BrN3O [M + H]+: 316.0085, found 316.0080.
4-cyano-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4b). Yield: (233 mg, 89%) ; white solid, Rf = 0.45 (Hex/EA =
3/2), mp: (225 – 227) °C. 1H NMR (500 MHz, CDCl3) δ 13.49 (s, 1H), 8.27 (dd, J = 1.3, 4.8 Hz, 1H), 8.04 (d, J = 8.9 Hz,
2H), 7.99 (dd, J = 1.3, 7.5 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 4.1 Hz, 1H), 7.17 (dd, J = 5.5, 8.2 Hz, 1H), 6.57 (d,
J = 4.1 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 164.8, 146.0, 141.9, 134.2, 132.2, 130.9, 130.1, 128.2, 120.3, 117.6, 117.1,
115.6, 100.0. IR(ATR) cm-1: 3138, 2955, 2919, 2850, 2225, 1687, 1548, 1365, 1224, 1047, 896, 795, 611, 503. HRMS (ESI):
calculated for C15H11N4O [M + H]+: 263.0933, found 263.0922.
4-fluoro-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4c). Yield: (221 mg, 87%) ; white solid, Rf = 0.4 (Hex/EA = 2/1),
mp: (182 – 184) °C. 1H NMR (500 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.25 (dd, J = 1.3, 4.8 Hz, 1H), 8.11 – 8.08 (m, 2H),
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8.04 (dd, J = 1.3, 7.5 Hz, 1H), 7.62 (d, J = 3.4 Hz, 1H), 7.45 -7.41 (m, 2H), 7.17 (dd, J = 4.8, 8.2 Hz 1H), 6.57 (d, J = 4.1
Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 165.2, 164.5 (d, JC,F = 250 Hz, C), 146.3, 143.2, 130.6, 130.5 (d, JC,F = 3.5
Hz, C), 129.0, 128.2, 118.5, 116.8, 115.8 (d, JC,F = 21.4 Hz, C), 98.5. IR(ATR) cm-1: 3141, 3072, 2919, 1686, 1599, 1541,
1498, 1363, 1267, 1161, 850, 714, 588. HRMS(ESI) : calculated for C14H11FN3O [M + H]+: 256.0886, found 256.0860.
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4-iodo-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4d). Yield: (329 mg, 91%) ; white solid, Rf = 0.45 (Hex/EA = 2/1),
mp: (194–196) °C. 1H NMR (500 MHz, CDCl3) δ 12.86 (s, 1H), 8.26 (dd, J = 1.3, 4.8 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H),
7.63-7.56 (m, 4H), 7.31 (d, J = 4.1 Hz, 1H), 7.13 (dd, J = 4.8, 8.2 Hz 1H), 6.52 (d, J = 4.1 Hz, 1H). 13C{1H} NMR (125 MHz,
CDCl3) δ 166.2, 146.1, 141.8, 137.6, 130.6, 130.3, 129.9, 129.0, 120.1, 116.9, 99.9, 99.6. IR(ATR) cm-1: 3490, 3430, 3185,
2919, 1668, 1582, 1565, 1481, 1362, 1272, 1004, 901, 761, 611, 500. HRMS (ESI): calculated for C14H10IN3ONa [M + Na]+:
385.9766, found 385.9760.
4-nitro-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4e). Yield: (267 mg, 95%) ; yellow solid, Rf = 0.3 (Hex/EA = 2/3),
mp: (258 – 260) °C. 1H NMR (500 MHz, CDCl3) δ 12.10 (s, 1H), 8.44 (d, J = 8.9 Hz, 2H), 8.27 – 8.24 (m, 3H), 8.05 (dd, J
= 1.4, 6.2 Hz, 1H), 7.66 (d, J = 3.4 Hz, 1H), 7.19 (dd, J = 4.5, 7.6 Hz, 1H), 6.60 (d, J = 3.4 Hz, 1H). 13C{1H} NMR (125
MHz, CDCl3): δ 164.8, 149.7, 146.1, 143.3, 137.2, 130.2, 129.3, 129.1, 123.9, 118.5, 116.8, 98.8. IR(ATR) cm-1: 3121,
3048, 2921, 1688, 1602, 1591, 1344, 1268, 1131, 1046, 852, 712, 605, 504. HRMS (ESI) : calculated for C14H10N4O3Na
[M + Na]+: 305.0651, found 305.0645.
4-chloro-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4f). Yield: (230 mg, 85%) ; white solid, Rf = 0.35 (Hex/EA =
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2/1), mp: (168 – 170) C. H NMR (500 MHz, DMSO-d6): δ 11.94 (s, 1H), 8.25 (d, J = 1.3, 4.8 Hz, 1H), 8.05 -8.03 (m,
3H), 7.68 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 3.4 Hz, 1H), 7.17 (d, J = 4.1, 7.5 Hz, 1H), 6.58 (d, J = 3.4 Hz, 1H). 13C{1H} NMR
(125 MHz, DMSO-d6) δ 165.3, 146.2, 143.2, 137.3, 130.4, 129.6, 129.1, 128.9, 118.5, 116.7, 98.6. IR(ATR) cm-1: 3126, 2927,
1670, 1594, 1562, 1486, 1362, 1273, 1088, 903, 848, 763, 718, 559, 506. HRMS (ESI) : calculated for C14H11ClN3O [M +
H]+: 272.0591, found 272.0584.
4-(tert-butyl)-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4g). Yield: (260 mg, 89%) ; Off-white solid, Rf = 0.35
(Hex/EA = 2/1), mp: (183 – 185) °C. 1H NMR (500 MHz, CDCl3) δ 12.3 (s, 1H), 8.28 (dd, J = 1.3, 4.8 Hz, 1H), 7.93 (dd,
J = 1.4, 7.5 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 3.4 Hz, 1H), 7.22 (d, J = 8.2 Hz 2H), 7.11 (dd, J = 4.8, 8.2 Hz,
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1H), 6.51 (d, J = 4.1 Hz, 1H), 1.28 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.9, 155.4, 146.4, 142.1, 130.6, 130.3, 127.8,
127.5, 125.3, 120.0, 116.9, 99.4, 34.9, 31.1. IR(ATR) cm-1: 3188, 2957, 2899, 1661, 1608, 1536, 1495, 1359, 1276, 1133, 1014,
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3,4-dimethoxy-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4h). Yield: (237 mg, 80%) ; Off-white solid, Rf = 0.35
(Hex/EA = 2/3), mp: (173 – 175) °C. 1H NMR (500 MHz, CDCl3): δ 11.67 (s, 1H), 8.24 (dd, J = 1.4, 4.8 Hz, 1H), 8.03 (dd,
J = 1.4, 7.5 Hz, 1H), 7.66 (dd, J = 1.4, 8.2 Hz, 1H), 7.60 – 7.58 (m, 2H), 7.17 (dd, J = 4.8, 8.2 Hz, 1H), 7.14 (d, J = 8.2 Hz
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1H), 6.56 (d, J = 4.1 Hz, 1H), 3.86 (s , 3H), 3.84 (s, 3H). C{1H} NMR (125 MHz, CDCl3): δ 165.7, 152.1, 148.4, 146.3,
143.1, 130.6, 129.0, 123.7, 121.2, 118.5, 116.6, 111.1, 110.6, 98.4, 55.6, 55.5. IR(ATR) cm-1: 3145, 2959, 2938, 2836, 1681, 1587,
1509, 1438, 1363, 1267, 1175, 1022, 858, 733, 590. HRMS (ESI) : calculated for C16H15N3O3Na [M + Na]+: 320.1011, found
320.1005.
4-methoxy-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4i). Yield: (216 mg, 81%) ; white solid, Rf = 0.35 (Hex/EA =
2/1), mp: (160 – 162) °C. 1H NMR (500 MHz, CDCl3): δ 12.68 (s, 1H), 8.27 (d, J = 4.1 Hz, 1H), 7.92 (dd, J = 1.3, 7.5 Hz,
1H), 7.89 (m, J = 8.9 Hz, 2H), 7.32 (d, J = 3.4 Hz, 1H), 7.10 (dd, J = 4.8, 8.2 Hz 1H), 6.70 (d, J = 8.9 Hz, 2H), 6.49 (d, J
= 3.4 Hz, 1H), 3.79 (s , 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 166.5, 162.5, 146.3, 142.0, 130.5, 130.2, 129.5, 128.1, 123.1,
119.9, 116.7, 113.5, 99.2, 55.3. IR(ATR) cm-1: 3238, 2932, 2837, 1672, 1606, 1506, 1365, 1256, 1176, 1019, 896, 761, 503.
HRMS(ESI) : calculated for C15H14N3O2 [M + H]+: 268.1086, found 268.1063.
4-methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4j). Yield: (200 mg, 80%) ; Off-white solid, Rf = 0.35 (Hex/EA
= 2/1), mp: (188 – 190) °C. 1H NMR (500 MHz, CDCl3) δ 12.48 (s, 1H), 8.27 (d, J = 4.1 Hz, 1H), 7.92 (dd, J = 1.3, 8.2 Hz,
1H), 7.78 (d, J = 7.5 Hz, 2H), 7.31 (d, J = 4.1 Hz, 1H), 7.10 (dd, J = 4.8, 8.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.49 (d, J =
3.4 Hz, 1H), 2.31 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.0, 146.2, 142.5, 142.0, 130.4, 130.2, 128.9, 127.9, 127.6,
119.8, 116.7, 99.2, 21.4. IR(ATR) cm-1: 3267, 3131, 2919, 2850, 1666, 1607, 1532, 1500, 1438, 1276, 1182, 908, 738. HRMS(ESI)
: calculated for C15H14N3O [M + H]+: 252.1137 found 252.1156.
4-(methylthio)-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4k). Yield: (223 mg, 79%) ; Off-white solid, Rf = 0.35
(Hex/EA = 2/1), mp: (189 -191) °C. 1H NMR (500 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.24 (dd, J = 1.3, 4.8 Hz, 1H), 8.03
(dd, J = 1.3, 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz 2H), 7.61 (d, J = 3.4 Hz, 1H), 7.43 (d, J = 8.9 Hz 2H), 7.17 (dd, J = 4.8, 7.5
Hz, 1H), 6.56 (d, J = 3.4 Hz, 1H), 2.56 (s , 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 165.8, 146.3, 144.2, 143.1, 130.6,
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129.0, 128.1, 127.5, 125.0, 118.5, 116.6, 98.4, 14.0. IR(ATR) cm-1: 3236, 2959, 2920, 1674, 1591, 1486, 1435, 1400, 1290, 1264,
1192, 1097, 1022, 894, 796, 715, 606. HRMS(ESI) : calculated for C15H13N3OSNa [M + Na]+: 306.0677, found 306.0670.
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N-(1H-pyrrolo[2,3-b]pyridin-1-yl)-2-naphthamide (4l). Yield: (238 mg, 83%) ; Off-white solid, RF = 0.35 (Hex/EA =
2/1), mp: (198 – 200) °C. 1H NMR (500 MHz, CDCl3): δ 12.01 (s, 1H), 8.68 (s, 1H), 8.27 (d, J = 3.4 Hz, 1H), 8.12 – 8.05
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(m, 4H), 7.70 -764 (m, 3H), 7.20 – 7.17 (m, 1H), 6.60 (d, J = 4.1 Hz 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.4, 146.3,
143.2, 134.6, 132.0, 130.6, 129.0, 128.5, 128.4, 128.2, 127.7, 127.1, 124.0, 118.6, 116.7, 98.5. IR(ATR) cm-1: 3521, 3205, 2919,
2849, 1665, 1555, 1511, 1437, 1362, 1281, 1195, 1140, 958, 914, 893, 864, 754, 719, 584, 475. HRMS(ESI): calculated for
C18H14N3O [M + H]+: 288.1137, found 288.1131.
N-(1H-pyrrolo[2,3-b]pyridin-1-yl)thiophene-3-carboxamide (4m). Yield: (216 mg, 89%) ; Off-white solid, Rf = 0.35
(Hex/EA = 2/1), mp: (217 – 219) °C. 1H NMR (500 MHz, CDCl3): δ 13.00 (s, 1H), 8.27 (dd, J = 1.35, 4.8 Hz, 1H), 8.11 (d,
J = 2.05 Hz, 1H), 7.94 (dd, J = 1.4, 7.55 Hz, 1H), 7.49 (d, J = 4.8 Hz 1H), 7.33 (d, J = 3.4 Hz, 1H), 7.13 – 7.11 (m, 2H), 6.51
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(d, J = 3.45 Hz, 1H). C{1H} NMR (125 MHz, CDCl3) δ 162.7, 146.3, 142.0, 134.1, 130.7, 130.6, 130.5, 126.6, 126.1,
120.1, 117.0, 99.5. IR(API, cm-1); 3139, 3107, 2904,2790, 1686, 1584, 1542, 1358, 1259, 1195, 1110, 1035, 946, 893, 862, 802,
776, 720, 595. HRMS(ESI) : calculated for C12H10N3OS [M + H]+: 244.0545, found 244.0565.
3-methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4n). Yield: (223 mg, 89%) ; Off-white solid, Rf = 0.35 (Hex/EA
= 2/1), mp: (200 – 202) °C. 1H NMR (500 MHz, CDCl3): δ 11.78 (s, 1H), 8.25 (dd, J = 1.35, 4.8 Hz, 1H), 8.04 (dd, J = 1.35,
8.2 Hz, 1H), 7.85-7.82 (m, 2H), 7.61 (d, J = 3.45 Hz, 1H), 7.47 (d, J = 6.15 Hz 2H), 7.17 (dd, J = 4.8, 7.6 Hz, 1H), 6.57 (d,
J = 4.1 Hz, 1H), 2.41 (s , 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 166.4, 146.3, 143.1, 138.0, 133.0, 131.7, 130.5, 129.0, 128.6,
128.2, 124.8, 118.5, 116.6, 98.5, 20.9. IR(ATR) cm-1: 3306, 3131, 2917, 1678, 1581, 1522, 1483, 1363, 1269, 1185, 1042, 922, 892,
799, 716, 687, 599, 505. HRMS(ESI) : calculated for C15H13N3ONa [M + Na]+: 274.0956, found 274.0950.
N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide-2,3,4,5,6-d5 {[D5] - 1a}
The corresponding Benzoic acid-2,3,4,5,6-d5 was dissolved in DMF and followed by addition of N-amino-7azindole,
EDC.HCl, HOBt and DIPEA respectively. The combined reaction mixture was stirred for 12h at room temperature.
After the completion, the reaction was diluted with EtOAc (2*30 mL) and then washed with water (5.0 mL), brine
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solution (5 mL) and dried over Na2SO4 filtered and concentrated in vacuum. The resulting residue was purified by
column chromatography to give the pure benzamide.
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Yield: (212 mg, 88%) ; Off-white solid, Rf = 0.35 (Hex/EA = 2/1), mp: (195 – 197) °C. 1H NMR (500 MHz, CDCl3): δ
12.90 (s, 1H), 8.27 (d, J = 3.8 Hz, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.31 (d, J = 3.4 Hz, 1H), 7.10 (d, J = 4.8, 8.2 Hz 1H), 6.49
(d, J = 4.1 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 166.8 146.2, 141.9, 130.4, 130.4, 130.3, 119.9, 116.7, 99.3. IR(ATR)
cm-1: 3598, 2982, 1678, 1582, 1523, 1441, 1363, 1270, 1046, 893, 849, 800, 773, 736, 717, 688, 599, 537. HRMS(ESI):
calculated for C14H7D5N3O [M + H]+: 243.1294, found 243.1289.
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General procedure for the ruthenium–catalyzed C(sp2)-H alkynylation/annulation
A 15 mL screw cap vial was equipped with magnetic stir bar and charged with N-(1H-pyrrolo[2,3-b]pyridin-1-
yl)benzamide (1a, 59.2 mg, 0.25 mmol), diphenyl acetylene (2a, 53 mg, 0.3 mmol), Ru(p-cymene)Cl2]2 (7.6 mg, 0.0125
mmol), AgSbF6 (8.5 mg, 0.025 mmol), Cu(OAc)2.H2O (100 mg, 0.5 mmol) and DCE (2.0 mL). The reaction was
sealed and kept under a preheated oil bath at 120 °C for 16h. The reaction was monitored with TLC and later reaction
tube was cooled to room temperature, the reaction mixture was diluted with 5 mL of dichloromethane and filtered
with a plug Celite bed, followed by washing with 20 mL of dichloromethane. The combined residue was
concentered under reduced pressure, and the resulting crude was purified by column chromatography to provide
the desired product 3a (85%).
3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3a). Yield: (87 mg, 85%) ; pale yellow solid, Rf =
0.55 (Hex/EA = 2/1), mp: (153 – 155) °C. 1H NMR (500 MHz, CDCl3): δ 8.52 (d, J = 7.55 Hz, 1H), 8.32 (dd, J = 1.4, 4.8
Hz, 1H), 7.78 (dd, J = 1.3, 7.5 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.29-7.16 (m, 6H), 7.12-.7.04 (m,
4H), 6.96 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 6.35 (d, J = 4.1 Hz, 1H). 13C{1H} NMR (125
MHz, CDCl3) δ 161.0, 146.7, 144.0, 141.9, 137.6, 135.5, 133.1, 132.2, 131.5, 131.3, 129.8, 129.7, 129.3, 128.6, 128.6, 128.2, 128.0,
127.8, 127.2, 127.1, 126.9, 125.9, 125.3, 119.2, 118.5, 117.0, 100.5. IR(ATR) cm-1: 3055, 2959, 2861, 1677, 1613, 1594, 1441, 1302,
1206, 1103, 1074, 1025, 964, 790, 774, 739, 696, 595. HRMS(ESI): calculated for C28H19N3ONa [M + Na]+: 436.1426,
found 436.1420.
3,4-bis(4-methoxyphenyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3b). Yield: (97 mg, 82%) ; Off-
white solid, Rf = 0.45 (Hex/EA = 1/1), mp: (110 – 112) °C. 1H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J = 8.2 Hz, 1H), 8.19
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(d, J = 4.1 Hz, 1H), 7.89 (dd, J = 4.1, 8.2 Hz, 1H), 7.77 (t, J = 8.2 Hz, 2H), 7.65 (d, J = 4.1 Hz, 1H), 7.62 (d, J = 8.2 Hz,
1H), 7.32 (dd, J = 2.0, 8.9 Hz, 1H), 7.19 – 7.16 (m, 2H), 7.12 (m, 2H), 6.86 - 6.83 (m, 3H), 6.58 (dd, J = 2.7, 11 Hz, 1H),
6.41 (d, J = 3.4 Hz, 1H), 6.27 (dd, J = 2.7, 8.2 Hz, 1H), 3.70 (s, 3H), 3.37 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6) δ
160.0, 158.4, 158.0, 146.3, 143.3, 142.3, 137.6, 133.6, 132.3, 132.2, 131.5, 130.4, 129.1, 127.6, 127.5, 127.3, 125.6, 124.5, 124.5,
118.1, 117.9, 117.0, 113.7, 113.6, 113.1, 112.3, 112.0, 99.6, 54.9, 54.7. IR(ATR) cm-1: 2951, 2958,2835, 1674, 1613, 1506, 1478,
1432, 1368, 1284, 1243, 1174, 1106, 1027, 827, 798, 772, 704, 561. HRMS (ESI): calculated for C30H23N3O3Na [M + Na]+:
496.1637, found 496.1631.
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3,4-bis(4-fluorophenyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3c). Yield: (82 mg, 73%) ; Off-white
solid, RF = 0.45 (Hex/EA = 2/1), mp: (97 – 99) °C. 1H NMR (500 MHz, DMSO-d6) δ 8.38 (dd, J = 1.4, 8.2 Hz, 1H), 8.24
(dd, J = 1.4, 4.8 Hz, 1H), 8.16 (dd, J = 1.4, 8.2 Hz, 1H), 7.93 (d, J = 3.4 Hz, 1H ), 7.88 – 7.84 (m, 1H), 7.72 (t, J = 7.5 Hz,
1H), 7.62 – 7.58 (m, 2H), 7.44 – 7.40 (m, 2H), 7.37 (d, J = 7.5 Hz, 1H), 7.24 (dd, J = 4.1, 7.5 Hz, 1H), 7.10 – 7. 06 (m,
2H), 6.79 (d, J = 4.1 Hz, 1H), 6.54 – 6.51 (m, 2H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 162.3 (d, JC, F = 248 Hz, C),
162.1 (d, JC, F = 244.4 Hz, C), 159.5, 146.1, 143.8, 135.7, 134.1, 133.0, 132.9 (d, JC,F = 9.5 Hz, C), 130.8, 130,0 129.5, 128.7,
128.1, 127.7, 125.8, 125.4, 123.0, 118.4, 117.4, 116.5, 116.2 (d, JC, F = 22.6 Hz, C), 115.6 (d, JC, F = 21.4 Hz, C), 99.9, 96.3, 80.5.
IR(ATR) cm-1: 3051, 1674, 1599, 1507, 1478, 1433, 1373, 1277, 1217, 1155, 1092, 993, 838, 796,771, 707, 539. HRMS(ESI):
calculated for C28H18F2N3O [M + H]+: 450.1418, found 450.1412.
3,4-bis(4-(tert-butyl)phenyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3d). Yield: (103 mg, 79%) ; Off-
white solid, Rf = 0.55 (Hex/EA = 2/1), mp: (183 – 185) °C. 1H NMR (500 MHz, CDCl3): δ 8.51 (dd, J = 1.4, 8.2 Hz, 1H),
8.33 (dd, J = 1.4, 4.8 Hz, 1H), 7.79 (dd, J = 1.4, 8.2 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.38 (t, J =
8.2 Hz, 1H), 7.23 (dd, J = 2.0 7.5 Hz, 1H), 7.16-7.11 (m, 2H), 7.09-7.05 (m, 2H), 7.01 (dd, J = 2.1, 8.2 Hz, 1H), 6.97-6.91
(m, 3h), 6.70 (d, J = 7.55 Hz, 1H), 6.35 (d, J = 3.4 Hz, 1H), 1.23 (s, 9H), 1.03 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ
161.1, 150.7, 149.7, 147.0, 144.0, 142.2, 137.7, 133.0, 132.6, 131.2, 130.9, 129.6, 129.3, 129.2, 128.8, 128.5, 126.9, 126.0, 125.2,
124.9, 124.4, 123.6, 119.4, 118.7, 117.0, 100.5, 34.3, 34.2, 31.1, 30.8. IR(ATR) cm-1: 3133, 2958, 2902, 1680, 1605, 1508, 1479,
1362, 1324, 1306, 1269, 1202, 1150, 1138, 1102, 1021, 965, 887, 832, 782, 772, 613, 57, 504. HRMS(ESI) : calculated for
C36H36N3O [M + H]+: 526.2858, found 526.2852.
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3,4-bis(4-chlorophenyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3e). Yield: (87 mg, 73%) ; Off-white
solid, Rf = 0.45 (Hex/EA = 3/2), mp: (140 – 142) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.35 (d, J = 7.5 Hz, 1H), 8.20 (d,
J = 4.1 Hz, 1H), 7.90 (d, J = 6.8 Hz , 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.69 – 7.66 (m, 2H), 7.46 (dd, J = 2.0, 8.2 Hz, 1H), 7.38
– 7.34 (m, 3H), 7.19 – 7.11 (m, 4H), 6.97 (dd, J = 2.0, 8.2 Hz, 1H), 6.584 (dd, J = 2.0, 8.2 Hz, 1H), 6.44 (d, J = 4.1 Hz,
1H). 13C{1H} NMR (125 MHz, CDCl3) δ 159.8, 146.1, 143.4, 141.2, 136.7, 134.0, 133.9, 133.1, 132.9, 132.2, 132.0, 131.0, 130.7,
130.2, 129.2, 128.4, 127.8, 127.8, 126.8, 125.5, 124.7, 118.0, 117.2, 117.0, 99.9. IR(ATR) cm-1: 3080, 2921, 2850, 1672, 1614,
1487, 1431, 1396, 1369, 1303, 1250, 1153, 1088, 1015, 963, 829, 758, 703, 673, 603, 491. HRMS(ESI) : calculated for
C28H18Cl2N3O [M + H]+: 482.0827, found 482.0821.
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3,4-bis(4-bromophenyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3f). Yield: (113 mg, 80%) ; Off-white
solid, RF = 0.55 (Hex/EA = 3/2), mp: (120 – 122) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.35 (d, J = 7.5 Hz 1H), 8.20 (d,
J = 3.4 Hz, 1H), 7.90 (dd, J = 1.4, 7.6 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.68 – 7.65 (m, 2H), 7.51 (dd, J = 2.05, 4.8 Hz,
2H), 7.40 (dd, J = 2.0, 8.2 Hz, 1H), 7.29-7.27 (m, 2H), 7.17-7.10 (m, 3H), 6.98 (dd, J = 2.0, 8.2 Hz, 1H), 6.91 (dd, J = 1.4,
8.2 Hz 1H), 6.45 (d, J = 4.1 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 159.8, 146.1, 143.4, 141.1, 136.6, 134.3, 133.9, 133.4,
133.2, 132.2, 131.3, 131.2, 131.1, 130.2, 130.1, 129.7, 129.2, 127.8, 127.7, 125.4, 124.6, 121.8, 120.9, 118.0, 117.2, 117.0, 99.9.
IR(ATR) cm-1: 2955, 2926, 2835, 1678, 1614, 1508, 1480 1287, 1246, 1176, 1029, 828, 772, 704. HRMS calculated for
C28H17Br2N3ONa (M + Na+): 591.9636, found 591.9617.
3,4-dimethyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3g). Yield: (52 mg, 72%) ; Off-white solid, Rf =
0.6 (Hex/EA = 2/1), mp: (190 – 192) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.22-8.19 (m, 2H), 8.11 (dd, J = 1.4, 7.6 Hz,
1H), 7.86 (d, J = 3.4 Hz, 1H), 7.77 (d, J = 4.1 Hz, 1H), 7.58 -7.55 (m, 1H), 7.23 (dd, J = 4.1, 7.6 Hz, 1H), 6.73 (d, J = 4.1 Hz,
1H), 2.34 (s , 3H), 1.98 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 160.2, 145.9, 143.8, 137.5, 137.2, 133.6, 130.0, 129.6,
127.6, 124.1, 123.7, 118.5, 117.4, 108.4, 100.1, 14.5, 13.6. IR(ATR) cm-1: 2919, 2850, 1663, 1615, 1481, 1431, 1371, 1330, 1299,
1275, 1159, 997, 795, 769, 727, 691, 518, 486. HRMS calculated for C18H15N3ONa [M + Na]+: 312.1113, found 312.1107.
3,4-diethyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3h). Yield: (55 mg, 70%) ; Off-white solid, Rf = 0.55
(Hex/EA = 2/1), mp: (158 – 160) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.20-8.18 (m, 2H), 8.11 (dd, J = 1.4, 7.6 Hz, 1H),
7.91-7.83 (m, 3H), 7.57-7.54 (m, 1H), 7.22 (dd, J = 4.1, 7.5 Hz, 1H), 6.73 (d, J = 3.4 Hz, 1H), 2.84 (q, J = 7.5 Hz, 2H),
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2.60-2.56 (m, 1H), 2.31-2.27 (m, 1H) 1.24 (t, J = 7.5, 3H), 0.97 (t, J = 7.6 3H). C{1H} NMR (125 MHz, DMSO-d6): δ
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160.2, 146.6, 143.6, 142.5, 136.2, 133.6, 131.0, 129.5, 127.8, 126.5, 124.5, 123.5, 118.6, 117.4, 114.3, 100.3, 21.7, 20.0, 14.8, 13.9.
IR(ATR) cm-1: 2976, 2919, 1671, 1609, 1474, 1427, 1366, 1330, 1272, 1220, 1093, 1058, 795,768, 697, 625, 505. HRMS
calculated for C20H20N3O [M + H]+: 318.1606, found 318.1635.
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3,4-dipropyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3i). Yield: (53 mg, 62%) ; Off-white solid, Rf =
0.55 (Hex/EA = 2/1), mp: (128 – 130) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.19 (d, J = 6.2, Hz, 2H), 8.12-8.10 (m, 1H),
7.87-7.82 (m, 3H), 7.56-7.54 (m, 1H), 7.22 (dd, J = 4.8, 8.2 1H), 6.73 (d, J = 3.4 Hz, 1H), 2.78 (q, J = 4.8 Hz, 2H), 2.55-
2.50 (m, 1H), 2.20-2.15 (m, 1H), 1.62 (q, J = 7.6, 2H), 1.45-1.37 (m, 2H) 1.08 (t, J = 6.9, 3H), 0.62 (t, J = 6.8, 3H). 13C{1H}
NMR (125 MHz, DMSO-d6): δ 160.2, 146.5, 143.6, 141.6, 136.4, 133.6, 130.9, 129.5, 127.8, 126.5, 124.5, 123.7, 118.5, 117.3,
113.3, 100.2, 30.4, 29.0, 23.2, 22.5, 14.1, 14.0. IR(ATR) cm-1: 2963, 2930, 2871, 1668, 1614, 1372, 1324, 1276, 1155, 1090, 1020,
888, 771, 739, 703, 592, 549. HRMS calculated for C22H24N3O [M + H]+: 346.1919, found 346.1916.
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4-methyl-3-phenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3j). Yield: (52 mg, 60%) ; Off-white solid,
Rf = 0.55 (Hex/EA = 3/2), mp: (150 – 152) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.32 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 4.8
Hz, 1H), 7.95-7.90 (m, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.68 -7.63 (m, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 7.2 Hz,
1H), 7.16 (t, J = 7.6 Hz, 1H), 7.10-7.06 (m, 2H), 6.99 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 3.4 Hz, 1H), 2.05 (s, 3H). 13C{1H}
NMR (125 MHz, DMSO-d6): δ 159.9, 146.1, 143.2, 141.1, 136.9, 133.8, 132.4, 130.4, 129.6, 129.0, 128.7, 128.6, 127.7,127.7,
127.4, 127.2, 124.8, 124.2, 118.0, 116.9, 110.0, 99.3, 14.5. IR (neat, cm-1): 2956, 2919, 2850, 1674, 1596, 1481, 1433, 1371, 1326,
1272, 1224, 769, 696, 596, 499. HRMS calculated for C23H18N3O [M + H]+: 352.1450, found 352.1442.
4-ethyl-3-phenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3k). Yield: (62 mg, 68%) ; Off-white solid, Rf
= 0.55 (Hex/EA = 2/1), mp: (158 – 160) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.33 (d, J = 7.6 Hz, 1H), 8.18 (dd, J = 1.4,
4.8 Hz, 1H), 7.97-7.92 (m, 2H), 7.85 (dd, J = 1.4, 7.6 Hz, 1H), 7.68 -7.62 (m, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.29 (t, J =
7.6 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.10-7.07 (m, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.34 (d, J = 3.4 Hz, 1H), 2.45 (q, J =
7.3Hz, 2H) 1.06 (t, J = 7.2, 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 159.8, 146.1, 143.2, 141.2, 135.8, 133.8, 132.1, 130.3,
129.4, 128.9, 128.7, 128.3, 127.7, 127.3, 127.2, 125.3, 124.1, 118.0, 116.9, 115.9, 99.4, 21.1, 14.6. IR (neat, cm-1): 2970, 2924.
2850, 1666, 1616, 1592, 1486, 1368, 1273, 1149, 1029, 793, 768, 700, 590, 503. HRMS calculated for C24H20N3O [M + H]+:
366.1606, found 366.1601. It was crystallized from dichloromethane.
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6-bromo-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5a). Yield: (86 mg, 70%) ; pale yellow
solid, Rf = 0.55 (Hex/EA = 3/2), mp: (168 – 170) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.27 (d, J = 8.9 Hz, 1H), 8.21
(dd, J = 1.4, 4.8 Hz, 1H), 7.87-7.83 (m, 2H), 7.67 (d, J = 4.15 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.30-7.27 (m, 3H), 7.25-
7.23 (m, 2H), 7.17 (d, J = 6.8 Hz, 1H), 7.11 (dd, J = 4.8, 7.5 Hz, 1H), 7.02 (t, J = 6.8 Hz, 1H), 6.94-6.89 (m, 2H), 6.71 (t, J
= 6.8 Hz, 1H), 6.39 (d, J = 3.4 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 159.5, 146.1, 143.9, 143.3, 138.8, 134.5, 131.7,
131.2, 131.0, 130.5, 130.2, 130.1, 130.0, 129.1, 129.0, 128.4, 128.3, 128.0, 127.6, 127.5, 126.9, 126.6, 123.5, 118.0, 117.1, 116.9, 99.8.
IR(ATR) cm-1: 3098, 3026, 2920, 1670, 1590, 1468, 1319, 1278, 1157, 1026, 800, 698. HRMS(ESI): calculated for
C28H19BrN3O [M + H]+: 492.0711, found 492.0704.
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1-oxo-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-1,2-dihydroisoquinoline-6-carbonitrile (5b). Yield: (75 mg, 69%) ;
pale yellow solid, Rf = 0.5 (Hex/EA = 3/2), mp: (253 – 255) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.49 (d, J = 8.2 Hz,
1H), 8.21 (d, J = 3.4 Hz, 1H), 8.04 (dd, J = 1.3, 8.2 Hz, 1H), 7.88 (dd, J = 1.3, 7.5 Hz, 1H), 7.68 (d, J = 3.4 Hz, 1H), 7.48 (d,
J = 1.3 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.32-7.24 (m, 4H), 7.18 (d, J = 6.9 Hz, 1H), 7.12 (dd, J = 4.8, 7.5 Hz 1H), 7.04 (t,
J = 7.6 Hz, 1H), 6.95-6.90 (m, 2H), 6.72 (t, J = 7.5 Hz, 1H), 6.41 (d, J = 3.4 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6)
δ 159.1, 146.1, 144.3, 143.4, 137.3, 134.1, 131.4, 131.2, 131.1, 130.0, 130.0, 129.9, 129.5, 129.2, 129.1, 128.9, 128.5, 128.4, 127.7,
127.1, 127.0, 126.6, 118.0, 118.0, 117.2, 117.1, 116.0, 100.0. IR(ATR) cm-1: 3055, 2923, 2853, 2223, 1682, 1611, 1561, 1476, 1429,
1369, 1324, 1262, 1185, 1030, 939, 870, 760. HRMS(ESI) : calculated for C29H18N4ONa [M+Na]+: 461.1378, found
461.1372.
6-fluoro-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5c). Yield: (70 mg, 65%) ; Off-white
solid, Rf = 0.5 (Hex/EA = 3/2), mp: (185 – 187) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.43 (dd, J = 6.2, 8.9 Hz, 1H), 8.21
(dd, J = 1.4, 4.8 Hz, 1H), 7.86 (dd, J = 1.3, 7.5 Hz, 1H), 7.68 (d, J = 3.4 Hz, 1H) 7.55-7.51 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H),
7.30-7.22 (m, 4H), 7.17 (d, J = 6.2 Hz 1H), 7.10 (dd, J = 4.8, 7.5 Hz, 1H), 7.02 (t, J = 6.8 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H),
6.90 (t, J = 7.5 Hz, 1H), 6.77 (dd, J = 2.7, 10.3 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.39 (d, J = 3.4 Hz, 1H). 13C{1H} NMR (125
MHz, DMSO-d6): δ 165.14 (d, JC,F = 250.3 Hz, C), 159.2, 146.2, 143.8, 143.3, 139.8 (d, JC,F = 9.5 Hz, C), 134.7, 131.7, 131.6
(d, JC,F = 38.1 Hz, C), 131.1 (d, JC,F = 15.5 Hz, C), 130.3, 130.0, 129.0 (d, JC,F = 14.3 Hz, C), 128.4, 128.3, 127.5, 126.9, 126.6,
121.5, 118.0, 117.3, 117.1, 116.1, 115.9, 110.6, 110.4, 99.8. IR(ATR) cm-1: 3053, 2921, 2852, 1683, 1618, 1581, 1468, 1432, 1371,
1273, 1213, 1153, 1068, 964, 888, 762, 698. HRMS calculated for C28H19FN3O [M + H]+: 432.1512, found 432.1507.
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6-iodo-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5d). Yield: (80 mg, 60%) ; Off-white
solid, Rf = 0.5 (Hex/EA = 3/2), mp: (243 – 245) °C. 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J = 4.8 Hz, 1H), 8.19 (d, J =
8.2 Hz, 1H), 7.84 (dd, J = 2.1, 8.9 Hz, 1H), 7.78 (dd, J = 1.4, 7.5 Hz, 1H), 7.63 (d, J = 1.4 Hz, 1H), 7.29-7.26 (m, 1H),
7.21-7.18 (m, 3H), 7.15-7.13 (m, 1H), 7.09-7.04 (m, 4H), 6.96 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.71 (t, J = 7.5
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Hz, 1H), 6.35 (d, J = 4.1 Hz 1H). C{1H} NMR (125 MHz, CDCl3): δ 160.7, 146.6, 144.1, 143.2, 138.9, 136.3, 134.7, 131.8,
131.4, 131.1, 130.0, 129.6, 129.5, 129.4, 128.4, 128.4, 128.2, 128.1, 127.4, 126.9, 124.4, 118.5,118.1, 117.2, 101.7, 100.7. IR(ATR)
cm-1: 2956, 2850, 1684, 1620, 1582, 1489, 1467, 1372, 1273, 1206, 1154, 1068, 964, 888, 833, 791. HRMS calculated for
C28H19IN3O [M + H] +: 540.0573, found 540.0566.
6-nitro-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5e). Yield: (83 mg, 73%) ; yellow solid, Rf
= 0.5 (Hex/EA = 3/2), mp: (207 – 209) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.59 ( (d, J = 8.25 Hz, 1H), 8.38 (dd, J =
2.0, 8.9 Hz, 1H), 8.21 (d, J = 4.1 Hz, 1H), 7.92 (dd, J = 2.1 Hz, 1H), 7.88 (d, J = 6.8 Hz, 1H), 7.70 (dd, J = 4.1 Hz, 1H),
7.43 (d, J = 7.5 Hz, 1H), 7.35-7.26 (m, 4H), 7.21 (d, J = 7.6 Hz, 1H), 7.12 (dd, J = 4.8, 7.5 Hz 1H), 7.05 (t, J = 7.5 Hz, 1H),
6.96-6.91 (m, 2H), 6.73 (t, J = 7.5 Hz, 1H), 6.42 (d, J = 3.4 Hz, 1H). 13C{1H} NMR (125 MHz, DMSO-d6): δ 159.0, 150.4,
146.0, 144.6, 143.4, 137.8, 134.2, 131.4, 131.2, 131.1, 130.2, 130.0, 129.9, 129.2, 128.9, 128.5, 128.2, 127.8, 127.0, 126.6, 121.2,
120.5 118.0, 117.7, 117.2, 100.0. IR(ATR) cm-1: 3056, 2921, 2851, 1687, 1593, 1524, 1490, 1348, 1210, 1144, 1070, 1029, 890,
835, 700, 597. HRMS calculated for C28H19N4O3 [M + H]+: 459.1457, found 459.1449.
6-chloro-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5f). Yield: (72 mg, 65%) ; Off-white
solid, Rf = 0.5 (Hex/EA = 3/2),mp: (172– 174) °C. 1H NMR (500 MHz, CDCl3): δ 8.45 (d, J = 8.2 Hz, 1H), 8.33 (dd, J =
1.4, 4.8 Hz, 1H), 7.78 (dd, J = 1.3, 8.2 Hz, 1H), 7.48 (dd, J = 2.0, 7.2 Hz, 1H), 7.29-7.24 (m, 2H), 7.21-7.19 (m, 2H), 7.15-
7.13 (m, 1H), 7.10-7.05 (m, 4H), 6.96 (t, J = 6.8 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.72 (t, J = 6.8 Hz, 1H), 6.36 (d, J = 3.4
Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 160.4, 146.6, 144.0, 143.4, 140.0, 139.0, 134.8, 131.9, 131.4, 131.1, 130.4, 129.6,
129.5,129.5, 128.5, 128.4, 128.3, 128.1, 127.7, 127.4, 127.0, 125.4, 123.7, 118.6, 118.4 117.2, 100.7. IR(ATR) cm-1: 3054, 2922,
2853, 1680, 1595, 1549, 1468, 1318, 1278, 1150, 1087, 968, 705. HRMS calculated for C28H19ClN3O [M + H]+: 448.1217,
found 448.1212.
6-(tert-butyl)-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5g). Yield: (94 mg, 81%) ; Off-
white solid, Rf = 0.5 (Hex/EA = 3/2), mp: (240 – 242) °C. 1H NMR (500 MHz, CDCl3): δ 8.45 (d, J = 8.2 Hz 1H), 8.31
(dd, J = 1.2, 4.6 Hz, 1H), 7.77 (dd, J = 1.4, 8.2 Hz, 1H), 7.59 (dd, J = 1.3, 8.2 Hz, 1H), 7.26-7.21 (m, 4H), 7.20-7.18 (m,
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2H), 7.11-7.04 (m, 4H), 6.96 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 7.0 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.35 (d, J = 4.1 Hz, 1H),
1.25 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 160.9, 156.8, 146.8, 144.0, 141.7, 137.4, 135.6, 132.4, 131.5, 131.2, 129.8, 129.7,
129.3, 128.8, 128.3, 128.1, 128.0, 127.7, 127.0, 126.9, 125.2, 123.0, 122.2, 119.5, 118.5, 117.0, 100.4, 35.3, 30.9. IR(ATR) cm-1:
3023, 2957, 2866, 1682, 1605, 1480, 1433, 1368, 1323, 1278, 1156, 1069, 1029, 846, 750, 694, 599. HRMS calculated for
C32H27N3ONa [M + Na]+: 492.2052, found 492.2049.
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6,7-dimethoxy-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5h). Yield: (94 mg, 80%) ; Off-
white solid, Rf = 0.5 (Hex/EA = 3/2), mp: (280 – 282) °C. 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J = 3.4 Hz, 1H), 7.90
(s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.26-7.25 (m, 2H), 7.19-7.17 (m, 3H), 7.12-7.05 (m, 4H) 6.95 (t, J = 7.5 Hz, 1H), 6.90 (t,
J = 6.8 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.63 (s, 1H), 6.35 (d, J = 3.4 Hz, 1H), 3.99 (s , 3H), 3.73 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3) δ 160.3, 153.8, 149.2, 146.9, 144.0, 140.6, 135.8, 133.1, 132.4, 131.4, 131.1, 129.9, 129.8, 129.3, 128.7, 128.2,
127.9, 127.8, 127.1, 126.9, 119.1, 118.8, 118.5, 117.0, 108.5, 106.4, 100.4, 56.1, 55.8. IR(ATR) cm-1: 3022,2973, 1665, 1600, 1489,
1392, 1272, 1212, 1113, 1072, 998, 876, 772, 716, 696, 570. HRMS calculated for C30H23N3O3Na[M + Na]+: 496.1637,
found 496.1631.
6-methoxy-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5i). Yield: (90 mg, 82%) ; Off-white
solid, Rf = 0.5 (Hex/EA = 3/2), mp: (203 – 205) °C. 1H NMR (500 MHz, CDCl3): δ 8.44 (d, J = 8.9 Hz, 1H), 8.32 (dd, J
= 1.4, 4.8 Hz, 1H), 7.76 (dd, J = 1.3, 7.5 Hz, 1H), 7.25-7.15 (m, 4H), 7.12-7.04 (m, 5H), 6.95 (t, J = 6.9 Hz, 1H), 6.89 (t, J
= 7.5 Hz 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H) 6.34 (d, J = 4.1 Hz, 1H), 3.73 (s, 3H). 13C{1H} NMR (125
MHz, CDCl3) δ 163.5, 160.7, 146.9, 144.1, 142.6, 139.9, 135.7, 132.4, 131.6, 131.3, 130.9, 129.8, 129.7, 129.4, 128.9, 128.3,
128.1, 128.0, 127.2, 127.0, 119.1, 119.0, 118.6, 117.1, 115.6, 108.3, 100.5, 55.4. IR(ATR) cm-1: 3051, 2935, 2835, 1672, 1607, 1482,
1374, 1232, 1176, 1133, 1031, 833, 769, 704, 576. HRMS calculated for C29H21N3O2Na [M + Na]+: 466.1531, found 466.1525.
6-methyl-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5j). Yield: (83 mg, 78%) ; Off-white
solid, Rf = 0.5 (Hex/EA = 3/2), mp: (206-207) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.25 (d, J = 8.2 Hz, 1H), 8.20 (d, J
= 4.8 Hz, 1H), 7.85 (dd, J = 1.3, 8.2 Hz, 1H), 7.67 (d, J = 3.4 Hz, 1H), 7.47 (dd, J = 1.3, 8.2 Hz 1H), 7.39 (d, J = 7.5 Hz,
1H), 7.27-7.24 (m, 3H), 7.21-7.15 (m, 2H), 7.09 (dd, J = 4.8, 8.2 Hz, 1H), 7.0 (t, J = 6.8 Hz, 1H), 6.95-6.92 (m, 2H), 6.88
(t, J = 7.5 Hz, 1H), 6.69 (t, J = 7.5 Hz, 1H), 6.37 (d, J = 3.4 Hz, 1H), 2.35 (s , 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ
159.8, 146.2, 144.0, 143.3, 142.4, 137.2, 135.3, 132.1, 131.2, 131.1, 130.4, 130.1, 129.1, 129.0, 128.9, 128.2, 128.0, 127.8, 127.2,
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126.8, 126.5, 125.1, 122.4, 118.0, 117.8, 117.0, 99.5, 21.7. IR(ATR) cm-1: 2921, 2864, 1676, 1612, 1556, 1479, 1370, 1321, 1279,
1148, 1110, 1055, 1032, 889, 831, 798, 722, 659, 504. HRMS calculated for C29H21N3ONa [M + Na]+: 450.1582, found
450.1575.
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6-(methylthio)-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5k). Yield: (90 mg, 79%) ; pale
yellow solid, Rf = 0.5 (Hex/EA = 3/2), mp: (84 – 86) °C. 1H NMR (500 MHz, CDCl3): δ 8.39 (d, J = 8.2 Hz, 1H), 8.33
(d, J = 4.8 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.36 (dd, J = 1.3, 8.2 Hz, 1H), 7.22-7.15 (m, 4H), 7.11-7.05 (m, 4H), 7.01 (d, J
= 1.4 Hz, 1H), 6.96 (t, J = 7.6 Hz 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 6.35 (d, J = 3.4 Hz, 1H), 2.37 (s,
3H). 13C{1H} NMR (125 MHz, CDCl3) δ 160.7, 146.6, 146.0, 143.8, 142.6, 137.8, 135.2, 132.1, 131.4, 131.1 129.6, 129.5, 129.4,
128.7, 128.2, 128.0, 127.8, 127.1, 126.8, 124.4, 121.9, 121.0, 118.6, 117.0, 100.4, 14.5. IR(ATR) cm-1: 3053,2920, 2864, 1672,
1591, 1473, 1432, 1370, 1319, 1276, 1205, 1154, 1069, 1032, 922, 772, 754. HRMS(ESI) : calculated for C29H22N3OS [M +
H]+: 460.1484, found 460.1470
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3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzo[g]isoquinolin-1(2H)-one (5l). Yield: (72 mg, 60%) ; Off-white
solid, Rf = 0.5 (Hex/EA = 3/2), mp: (323 – 325) °C. 1H NMR (500 MHz, CDCl3): δ 9.13 (s, 1H), 8.34 (d, J = 4.1 Hz, 1H),
8.06 (d, J = 7.6 Hz, 1H), 7.77 (t, J = 6.9 Hz, 2H), 7.69 (s, 1H), 7.56-7.51 (m, 2H), 7.30 (d, J = 2.7 Hz, 2H), 7.24-7.22 (m,
3H), 7.13-7.11 (m, 3H), 7.06 (dd, J = 4.8, 7.6 Hz 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.71 (t, J = 7.5 Hz,
1H), 6.35 (d, J = 4.1 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 161.6, 146.8, 143.9, 140.7, 135.9, 135.6, 133.5, 132.3, 131.6,
131.4, 130.2, 129.9, 129.8, 129.3, 128.8, 128.4, 128.2, 128.1, 128.0, 127.9, 127.1, 126.9, 126.8, 126.5, 125.0, 123.5, 119.2, 118.5,
117.0, 100.4. IR(ATR) cm-1: 3053, 2972, 1671, 1622, 1593, 1489, 1441, 1361, 1272, 1204, 1182, 1056, 1032, 967, 887, 793, 721,
696. HRMS calculated for C32H22N3O [M + H]+: 486.1576, found 486.1576
6,7-diphenyl-5-(1H-pyrrolo[2,3-b]pyridin-1-yl)thieno[3,2-c]pyridin-4(5H)-one (5m). Yield: (74 mg, 71%) ; Off-white
solid, Rf = 0.5 (Hex/EA = 3/2), mp: (206 – 208) °C. 1H NMR (500 MHz, CDCl3): δ 8.34 (dd, J = 2.0, 4.8 Hz, 1H), 7.79
(dd, J = 1.4, 7.5 Hz, 1H), 7.76 d, J = 5.5 Hz, 1H) 7.34 (d, J = 5.5 Hz, 1H), 7.28-7.20 (m, 5H), 7.14-7.12 (m, 1H), 7.08-7.06
(m, 3H), 7.00-6.94 (m, 2H), 6.76 (t, J = 6.85 Hz, 1H), 6.37 (d, J = 4.1 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 157.2,
151.2, 146.8, 144.1, 141.9, 136.0, 131.5, 130.0, 129.8, 129.4, 129.1, 128.7, 128.4, 128.3, 127.7, 126.1, 125.8, 118.5, 117.1, 116.7, 100.6.
IR(ATR) cm-1: 3050, 2971, 2855, 1675, 1581, 1561, 1478, 1427, 1366, 1275, 1054, 1032, 1013, 919, 794, 769, 725, 669. HRMS
calculated for C26H18N3OS [M + H]+: 420.1171, found 420.1153
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7-methyl-3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (5n). Yield: (75 mg, 71%) ; Off-white
solid, Rf = 0.5 (Hex/EA = 3/2), mp: (177 – 179) °C. 1H NMR (500 MHz, DMSO-d6): δ 8.20 (d, J = 4.8 Hz, 1H), 8.16 (s,
1H), 7.86 (dd, J = 1.35, 7.5 Hz, 1H), 7.67 (d, J = 3.4 Hz, 1H), 7.62 (dd, J = 2.0, 8.2 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.29-
7.24 (m, 3H), 7.20 (d, J = 6.9 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.11-7.07 (m, 2H), 7.0 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 7.6
Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H ), 6.69 (t, J = 6.8 Hz, 1H), 6.37 (d, J = 3.4 Hz, 1H), 2.48 (s, 3H). 13C{1H} NMR (125 MHz,
DMSO-d6): δ 159.8, 146.2, 143.2, 141.3, 137.3, 135.4, 134.9, 134.8, 132.0, 131.2, 131.0, 130.4, 130.2, 129.2, 129.0, 128.1, 128.0,
127.2, 126.8, 126.5, 125.6, 124.6, 118.0, 117.8, 116.9, 99.5, 20.8. IR(ATR) cm-1: 3100, 3052, 2921, 2859, 1669, 1612, 1590, 1494,
1442, 1372, 1324, 1270, 1222, 1136, 1032, 831, 794, 770, 716, 693. HRMS calculated for C29H22N3O [M + H]+: 428.1763,
found 428.1752
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Genereal procedure for the directing group removal
To a solution of 3,4-diphenyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)isoquinolin-1(2H)-one (3a) ( 50 mg, 0.12 mmol) in
EtOH (3 mL), N2H4.H2O (30 mg , 0.6 mmol) was added and the resulting mixture was stirred at room temperature
for 2 h. After the completion of the reaction, the solvent was evaporated under reduced pressure. The resultant
residue was subjected to silica gel column chromatography ( EtOAc/Hexane – 2:3) to afford 28 mg (80 %) of 3,4-
diphenylisoquinolin-1(2H)-one (3aa) as white solid.10 1H NMR (500 MHz, DMSO): δ 11.57 (s, 1H), 8.31 (d, J = 7.5
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Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.29-7.13 (m, 11H). C{1H} NMR (125 MHz, CDCl3): δ 161.7,
138.5, 138.1, 135.8, 134.5, 132.5, 131.7, 129.8, 128.2, 128.2, 127.7, 127.0, 126.8, 126.2, 125.0, 124.9, 115.4.
3,4-dimethylisoquinolin-1(2H)-one (3gg). Yield: (16 mg, 79%) ; pale red solid, Rf = 0.5 (Hex/EA = 3/2), mp: 258 – 260
°C. 1H NMR (500 MHz, CDCl3): δ 10.48 (s, 1H), 8.44 (d, J = 7.5 Hz, 1H), 7.70-7.65 (m, 2H), 7.47-7.44 (m, 1H), 2.40 (s,
3H), 2.26 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 163.4, 138.9, 133.0, 132.5, 127.5, 125.4, 124.6, 122.7, 108.3, 17.6, 12.5.
IR(ATR) cm-1: 3161, 2987, 2865, 1633, 1605, 1547, 1475, 1170, 1009, 912, 763, 705, 652. HRMS calculated for C11H11NONa
[M + Na]+: 196.0738, found 196.0733.
6-(methylthio)-3,4-diphenylisoquinolin-1(2H)-one (5kk). Yield: (33 mg, 82%) ; white solid, Rf = 0.5 (Hex/EA = 3/2),
mp: 281 – 283 °C. 1H NMR (500 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.39 (dd, J = 1.3, 8.2 Hz, 1H),
7.30-7.20 (m, 8H), 7.14 (d, J = 6.9 Hz, 2H), 6.85 (d, J = 1.3 Hz, 1H), 2.35 (s, 3H). 13C{1H} NMR (125 MHz, DMSO-d6): δ
161.4, 144.2, 139.4, 138.4, 135.5, 134.4, 131.7, 129.7, 128.2, 127.7, 127.4, 127.1, 123.5, 121.8, 119.9, 114.7, 13.9. IR(ATR) cm-1:
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3100, 3052, 2921, 2859, 1669, 1612, 1590, 1494, 1442, 1372, 1324, 1270, 1222, 1136, 1032, 831, 794, 770, 716, 693. HRMS
calculated for C22H18NOS [M + H]+: 344.1109, found 344.1107.
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Synthesis of the ruthenium complex – 4j’
A mixture of 4-methyl-N-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (4j) (0.050 g, 0.2 mmol), [Ru(p-cymene)Cl2]2
(0.122g, 0.2 mmol), and NaOAc (0.033g, 0.4 mmol) was taken in MeOH (10 mL) and heated under reflux for 2 h at
80 °C. The reaction was monitored by TLC and solvent was concentrated in vacuo, and the product was purified
by column chromatography on silica gel using dichloromethane : methanol as eluent to afford the ruthenium
complex-4j’ in 41 mg (40 %) yield.. The product was recrystallized from dichloromethane–hexane (1:1) mixture.
Yield: (41 mg, 40%) ; deep red crystals, Rf = 0.35 DCM/MeOH (2/1), mp: 205 – 207 °C. 1H NMR (500 MHz, CDCl3):
δ 9.02 (d, J = 3.4 Hz, 1H), 8.16 (d, J = 5.5 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.91(d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.2 Hz,
1H), 7.08 (dd, J = 5.5, 7.5 Hz, 1H), 6.49 (d, J = 4.1 Hz, 1H), 5.23 (d, J = 6.2 Hz, 1H), 5.07 (d, J = 5.5 Hz, 1H), 4.89 (d, J =
6.1 Hz, 1H), 3.90 (d, J = 5.5 Hz, 1H), 2.45 (s, 3H), 2.45-2.42 (m, 1H), 2.16 (s, 3H), 0.98 (d, J = 6.9 Hz, 3H), 0.92 (d, J =
6.9 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 174.6, 145.5, 142.4, 139.5, 138.0, 131.6, 130.2,129.7, 128.4, 116.6, 115.0, 98.5,
84.5, 82.6, 30.6, 22.6, 21.5, 21.4, 18.8. IR(ATR) cm-1: 3163, 2967, 2880, 1615, 1579, 1495, 1345, 1298, 1179, 1083, 934, 797.
HRMS (ESI) calculated for C25H26N3ORu [{M –Cl}]+: 486.1119, found 486.0893.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
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Mechanistic details, copies of all H NMR & C NMR spectra for all new compounds and X-ray crystallographic
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Accession Codes
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CCDC 1868212, 1868597 & 1913752 contains 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,
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Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
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Corresponding Author
* E-mail: pcr@niser.ac.in.
ORCID
Prateep Singh Sagara: 0000-0002-1860-9020
Prem Felix Siril: 0000-0002-8818-7310
P. C. Ravikumar: 0000-0002-5264-820X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are thankful to Advanced Materials Research Center (AMRC), IIT Mandi for facilities. We acknowledge
financial support from DST, CSIR (02(0256)/16EMR-II), SERB (EMR-II/2017/001475). P.S.S acknowledge research
fellowship (SRF) from University Grants Commission, Government of India. We are thankful to Dr. Subrata Ghosh,
IIT Mandi and Dr. Asit Ghosh, NISER Bhubaneswar for helpful suggestions. We are also thankful to Mr. Puneet
Sood for his help in solving X-ray data and Mr. Shyam Kumar Banjare for cross checking and minor corrections.
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