Pd-Catalyzed Sequential Arylation of 7-Azaindoles: Aggregate-Induced Emission of Tetra-Aryl 7-Azaindoles

Article abstract of DOI:10.1021/acs.joc.9b02187

Pd-catalyzed synthesis of multi-aryl 7-azaindoles using sequential arylation of 5-bromo-6-chloro-3-iodo-1-methyl-1H-pyrrolo[2,3-b] pyridine is established. Four diverse aryl groups are installed in a chemo-selective fashion providing a general method to synthesize sterically encumbered compounds and extended 7-azaindoles in 48-95% yields. Three-selective sequential arylations at C-3, C-5, and C-6 via Suzuki-Miyaura cross-coupling followed by direct C-2 arylation using a Pd catalyst and AgOTf as an additive are highlights of the present work. Interestingly, the tetra-aryl 7-azaindoles showed aggregate-induced emission (AIE) making it potentially useful as fluorophores in OLEDs, sensors, and bio-imaging tools.

Full text of DOI:10.1021/acs.joc.9b02187

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Article
Pd-Catalyzed Sequential Arylation of 7-azaindoles:
Aggregate Induced Emission of Tetra-aryl 7-azaindoles
Savio Cardoza, Parthasarathi Das, and Vibha Tandon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02187 • Publication Date (Web): 16 Sep 2019
Downloaded from pubs.acs.org on September 16, 2019
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Pd-Catalyzed Sequential Arylation of 7-azaindoles:
Aggregate Induced Emission of Tetra-aryl 7-azaindoles
Savio Cardoza,† Parthasarathi Das,§,* Vibha Tandon†,*
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† Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067
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§ Department of Applied Chemistry, Indian Institute of Technology (Indian School of mines), Dhanbad,
Jharkhand-826004
E-mail: vtandon@mail.jnu.ac.in ; partha@iitism.ac.in
1st Suzuki-Miyaura
C-C coupling
OCH3
12 examples
40-70 % yields
2nd Suzuki-Miyaura
H3
C
C-C coupling
12 examples
66-88 % yields
Ar1
Ar2
Ar3
N
N
CH3
Ar4
3rd Suzuki-Miyaura
N
N
C-C coupling
11 examples
42-79 % yields
C-H activation
6 examples
PG
48-95 % yields
PG = Me, PMB
Pd catalyzed
sequential arylation
AIE characteristics
ABSTRACT
Pd-catalyzed synthesis of multi-aryl 7-azaindoles using sequential arylation of 5-bromo-6-chloro-3-
iodo-1-methyl-1H-pyrrolo[2,3-b] pyridine is established. Four diverse aryl groups are installed in
chemo-selective fashion providing a general method to synthesize sterically encumbered compounds
and extended 7-azaindoles in 48 – 95% yield. Three selective sequential arylations at C-3, C-5 and C-6
via Suzuki-Miyaura cross-coupling followed by direct C-2 arylation using Pd catalyst and AgOTf as an
additive are highlights of the present work. Interestingly the tetra-aryl 7-azaindoles showed aggregate
induced emission (AIE) making it potentially useful as fluorophores in OLEDs, sensors and bio-
imaging tools.
Keywords: Tetra-aryl 7-azaindoles, Sequential arylation, Sequential Suzuki-Miyaura cross-coupling,
Aggregate induced emission.
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1. INTRODUCTION
Sequential arylation of arenes/ hetero-arenes is widely known to furnish favourable
optoelectronic1 and medicinal properties2 into designed molecules. Such diversity-oriented synthesis has
the potential to build a vast molecular library to investigate structure-activity properties. Transition
metal catalyzed arylation on arene/ heteroarene templates in a predictable manner3 has garnered
attention to obtain diverse π-conjugated organic molecules.4
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O
S
HN
CF3
F
N
NH2
O
Cl
O
O
C
S
N
F
O
H
N
N
N
N
H
H
B-Raf inhibitor (Vemurafenib)
Trk Inhibitor
N
N
N
B
CHO
F
F
N
N
N
C12H25
N
H
HSO4- anion sensor
Solid-state emitter in OLED
Figure 1. Biological and Material applications of substituted 7-azaindole6,7,8
A review in 2014 showcased various N-heterocycles where substitution pattern plays an
astounding role in its biological activity.5 Significant substitutions on fused pyrrole and pyridine ring
has put 7-azaindoles on a list of privileged scaffolds in drug discovery (Figure 1).6 Proton donor and
acceptor functionality present on these moieties help in studying its photophysical properties.7 Recently
C-arylated 7-azaindoles have exhibited desirable applications in organic light emitting molecules and
sensors (Figure 1).8 Propeller-like organic frameworks having peripheral phenyl/aryl groups with
different electronic characteristics show aggregation induced emission (AIE) phenomena attracting
material chemists all over the globe.9 In view of the above, it remains imperative to explore the
synthesis of multi-aryl 7-azaindole derivatives for applications in medicinal and material sciences.
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Directed metalation, halogen/magnesium exchange and sulfoxide/magnesium exchange
reactions were developed by Knochel et. al. and recently elaborated by Snieckus et. al. to selectively
introduce various functional groups on the 7-azaindole ring.10 Selective mono/di-arylations at different
positions of 7-azaindoles is normally achieved by de-novo approaches and metal catalyzed cross-
coupling of 7-azaindoles reporting very few examples with heteroaryl substrates.11 Das et. al.
synthesized C-2, C-3 and C-5 tri-aryl 7-azaindoles sequentially, requiring pre-functionalization at an
intermediate step.3c Adhering to a de-novo approach, Yamaguchi et. al. have synthesized tetra-aryl 7-
azaindole and hepta-aryl indoles (Scheme 1). Their method required alkylation, Suzuki-Miyaura cross-
coupling \and S-oxidation of synthesized C-2, C-6 di-aryl thiophenes, followed by ring transformation
of substituted thiophene-S,S′-dioxides.3i In contrast to the previous reports we envisaged to synthesize
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Previous work (Yamaguchi 3i)
Ar2
Ar3
Ar2
Ar4
Ar2
[Sc],[Zn]
Ar4
Ar1
C-5 alkylation
Suzuki-Miyaura
m-CPBA
Ar3
Ring
transformation
Ar1
S
S
Ar1
N
N
O
O
Ts
NRTs
R = -H,-CN
Tetra-aryl 7-azaindole (one example)
Cross Coupling
Br
This work
Ar1
I
Ar2
I
Br
Cl
[Pd]
H
Ar4
H
N
N
N
Cl
N
N
N
Ar3
PG
PG
PG
C-H activation
Ar1/Ar2/Ar3/Ar4 = aryl/heteroaryl
Cross Coupling
PG = Me, PMB
Scheme 1. Synthetic Approaches for tetra-aryl 7-azaindoles
designed tetra-aryl 7-azaindoles from tri-halogenated 7-azaindole (5), a common synthetic template.
Such sequential routes to synthesize tetra-aryl 7-azaindoles are rare in literature. We endeavoured to
synthesize structurally diverse and sterically hindered tetra-aryl derivatives via four step Pd catalyzed
C-C cross-coupling protocol. Three sequential and selective Suzuki-Miyaura cross-coupling reactions
with aryl/hetero-aryl substrates followed by C-2 arylations are studied. Structural features of these tetra-
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aryl derivatives led us to investigate its aggregate induced emission profile of C-arylated 7-azaindoles,
broadening its scope in materials research.
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2. RESULTS AND DISCUSSIONS
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I
Br
Br
Cl
Br
Cl
Br
Br
(iv)
(ii)
(iii)
(i)
N
N
N
N
N
N
N
N
N
N
O
3
H
H
H
H
PG
2,
90%
1
4
, 42 %
, 87 %
PG
Yield
(i) NIS, DCM, r.t.,1h
5
Method A: Me
, 68%
5
(ii) mCPBA, Et2O, r.t., 1 h; then aq. K2CO3, r.t., 12 h
(iii) Cl3COCl, HMDS, r.t., 1 h
(iv) Method A : NaH, CH3I, r.t.,3 h
Method B: PMB , 53%
Method B : K2CO3, p-methoxybenzyl chloride, r.t.,6 h
Scheme 2. Synthetic route for 5 and 5ʹ
The precursor 5-bromo-6-chloro-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (5/5ʹ) was
synthesized (Scheme 2) starting from 5-bromo-7-azaindole (1) via iodination at C-3 position (2), N-
oxidation of azine ring (3), chlorination at electrophilic C-6 position (4) and finally N-H protection by
methyl (5) or p-methoxy benzyl (5ʹ). This tri-halogenated derivative forms a template to investigate
sequential Suzuki-Miyaura arylation and subsequent C-2 arylation. C-3 selective mono-arylation was
first studied due to the preferential oxidative-addition towards Ar-I >Ar-Br >Ar-Cl 12. The Suzuki-
Miyaura coupling of 5 with phenyl boronic acid (1.0 equiv.) was studied using Pd2dba3 (5 mol%),
XPhos (5 mol%) as catalytic system and base Cs2CO3 (2 equiv.) in toluene: ethanol (1:1) at 60°C.
Stirring for 15 min the reaction yielded 42% of the desired C-3 mono-arylated product, 6a and
undesired 51% di-aryl product (6aa), thus revealing non-selectivity between –iodo and –bromo groups
towards the Pd catalyzed oxidative addition (Table 1, entry 1). In order to make this method selective
we conducted various experiments, screening different reaction parameters. SPhos was used as ligand
and 6a was isolated in 44% yield and 6aa in 42% yield (entry 2). The reaction yielded 49% of 6a and
9% of 6aa at room temperature (entry 3). Changing the catalyst to Pd(OAc)2 yielded higher quantity of
di-aryl 6aa (59%) as compared to 6a (25%) at r.t. (entry 4) and Pd(PPh3)4 yielded a low 18% of 6a and
30% of 6aa at r.t. (entry 5). Bidentate 1,1'-bis(diphenylphosphino) ferrocene (dppf, 5 mol%) was used
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as ligand instead of SPhos to obtain desired 6a in 62% yield (entry 6), whereas, 6aa was not
4
5
synthesized.
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Table 1. Optimization table for selective Suzuki-Miyaura arylation at C-3 position of 5a
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B(OH)2
Catalyst (5 mol %)
Ligand (5 mol %)
Cs2CO3 (2 equiv.)
I
Br
Cl
Br
Cl
N
CH3
N
CH3
N
CH3
N
Solvent
T°C, 0.5 h
N
Cl
N
6a
6aa
5
Yield (%)
b
Entry
Catalyst
Ligand
Solvent (v:v)
T °C
6a : 6aa
42 : 51
44 : 42
49 : 9
25 : 59
18 : 30
62 : 0
47 : 0
23 : 0
74 : 0
35 : 0
30 : 0
72 : 9
54 : 0
76 : 0
56 : 0
50 : 0
1
2
Pd2dba3
Pd2dba3
Pd2dba3
Pd(OAc)2
Pd(PPh3)4
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
Pd2dba3
XPhos
SPhos
SPhos
SPhos
SPhos
dppf
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
Dioxane : Water (3:1)
THF : Water (1:1)
Toluene:Ethanol (1:1)
Toluene:Ethanol (1:1)
Toluene : Ethanol (3:1)
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
Toluene : Ethanol (1:1)
60 °C
60 °C
r.t.
3
4
r.t.
5
r.t.
6
r.t.
7
dppf
r.t.
8
dppf
r.t.
9
dppf
dppf
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
10c
11
12d
13
14e
15
16
dppf
dppf
dppe
P(OC6H5)3
DPEPhos
XantPhos
aReaction conditions: 5 (0.046 g, 0.124 mmol, 1 equiv.), Phenyl boronic acid (0.015 g,0.124 mmol, 1 equiv.), Catalyst (5 mol
%,0.0062 mmol ), Ligand (5 mol %, 0.0062 mmol), Cs2CO3 (0.248 mmol,2 equiv.), Solvent (2 mL, 0.062 M), T °C, 0.25 h.
bIsolated yields of 6a and 6aa.c Pd2dba3 (5 mol %), dppf (10 mol%) d Pd2dba3 (10 mol %), dppf (10 mol %). e Reaction time =
0.5 h.
Examining different solvent systems gave unfavourable results i.e. Dioxane: water (3:1) gave 47% of 6a
(entry 7) and THF: water (1:1) produced a low 23% yield for 6a (entry 8). Fortunately, at 60 °C, the
reaction yielded 74% of 6a with eliminated non-selectivity (entry 9). The usage of a different Pd:L ratio
also was significant as 5 mol% Pd2dba3 and 10 mol% dppf gave 6a in 35% yield (entry 10). It was also
observed that decreasing the ethanol in solvent mixture i.e. 3:1 toluene: ethanol decreased the yield of
6a (entry 11). Increasing the catalyst loading and ligand to 10 mol% was of no advantage as di-aryl 6aa
was formed in 9% yield (entry 12). Further various electron poor ligands were used for optimizations.
1,2-Bis(diphenylphosphino)ethane as ligand provided 6a in 54% yield (entry 13) and triphenyl
phosphite a monodentate highly π-acidic ligand was used instead of dppf and 6a was isolated in 76%
yield (entry 14) with reaction time being 30 min. DPEPhos and XantPhos were tested as ligand in above
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conditions giving 6a in 56% and 50% yield (entry 15-16). After careful optimization reactions, Pd2dba3
(5 mol%), dppf (5 mol%) was chosen as the best catalytic system for C-3 SMC (Suzuki-Miyauara cross-
coupling) in toluene: ethanol (1:1) stirring at 60 °C for 15 min.
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Substrate scope for C-3 SMC arylation with different aryl/hetero-aryl boronic acids (Scheme 3)
was explored. The phenyl group was incorporated in 74% yield (6a) and moderate yield of 53% for p-
methoxy benzyl N-protected 7-azaindole (6aʹ). Electron donating 4-methyl (6b) and 4-methoxy
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Scheme 3. Scope for C-3 selective mono-arylation of 5. a
Pd2dba3 (5 mol %)
Ar1
dppf (5 mol %)
I
Ar1- B(OH)2 (1.0 equiv.)
Br
Br
Cs2CO3 (2 equiv.)
N
Cl
N
N
Toluene:Ethanol (1:1)
60°C, 0.25 h
Cl
N
CH3
CH3
6a-i, 6a' b
5
CH3
OCH3
F
OCH3
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
N
N
N
N
N
CH3
,70 %
N
N
R
N
N
N
CH3
6a
R = Me, , 74 %
CH3
, 40 %
CH3
6e
, 65 %
c
6b
6c
, 64 %
6d
6a'
R = PMB, , 53 %
O
O
Br
Cl
Br
Cl
Br
Cl
Br
Cl
N
N
N
CH3
, 51 %
N
N
N
N
N
CH3
, 69%
CH3
CH3
6i
, 45%
6h
6g
, 63 %
6f
CHO
S
Br
Cl
Br
Cl
N
CH3
N
N
N
CH3
6j
, 40 %
6k
, 70 %
a Reaction conditions: 5 (0.186 g, 0.5 mmol, 1 equiv.), Ar1-B(OH)2 (0.5 mmol, 1 equiv.), Pd2dba3 (0.025 mmol, 5 mol%), dppf (0.025
mmol, 5 mol%), Cs2CO3 ( 1 mmol, 2 equiv.), Toluene: ethanol (1:1, 5 mL, 0.1 M), T = 60 °C, 0.25 h. b Isolated yields of 6a-6i, 6aʹ; c
PMB: p-methoxy benzyl, reaction was done at rt.
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substituted (6c) phenyls were installed at C-3 in 64% and 70% yields respectively whereas meta-
substituted methoxy phenyl boronic acids gave 6d in moderate yield of 40%. Electron-withdrawing 4-
fluoro substituted boronic acids coupled with 5 to form 6e in 65% yield which shows that C-3 SMC
arylation is efficient for electronically different boronic acids (6a-c, 6e). Boronic acids containing
bicyclic naphtyl and benzo[d][1,3]dioxole formed corresponding products 6f and 6g in 51% and 63%
yields respectively and sterically hindered 1-naphthyl (6h) and 1-pyrene (6i) groups were incorporated
in good yields (45-69%). In addition to it, present methodology showed efficient coupling of 3-thienyl
boronic acid yielding 70% of 6j and tolerance towards formyl functional group as exemplified by 6k.
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The C-5 arylation was next investigated for C-3 mono-aryl derivatives (Table 2). Studies
commenced with SMC reaction between 6a and 4-methoxy phenyl boronic acid (1 equiv.) using
Pd2dba3 (5 mol%), dppf (10 mol%) and Cs2CO3 (2 equiv.) in toluene: ethanol mixture (1:1). The
reaction was stirred at 60 °C for 2 h to yield di-aryl product (7a) in 37% yield but a major obstacle was
proto-dehalogenation13 at C-5 position producing 7aa in 47% yield (Table 2, entry 1). Increasing the
temperature and catalyst loading was of no advantage producing undesirable 7aa in 59% and 39% yield
respectively (entries 2-3). Solvent ratio was changed to use a less polar toluene: ethanol (3:1) giving 7a
in 20% yields and comparatively lower yield of 7aa (13%) with conversion being 38% (entry 4).
Moving forward we adopted 1,4-Dioxane: water (3:1) as solvent system favourably yielding 31% 7a
and 0% 7aa but reactant conversion is 56% (entry 5). Further, decreasing the water fraction, an
enhanced yield for 7a (84%) was observed along with complete conversion of reactant (entry 6). 1,4-
dioxane: water (8:1) was also examined as solvent but 7a was isolated in 46% yield (entry 7). Finally,
combination of 10 mol% Pd2dba3 with 20 mol% dppf, 2 equiv. Cs2CO3 stirred in 1, 4-dioxane: water
(6:1) for 2h at 100 °C was found to be the preferred reaction conditions for C-5 SMC arylation. With
the optimized protocol in hand, the substrate scope for C-5 SMC arylation was evaluated (Scheme 4).
Boronic acids with electron donating and electron withdrawing substituents led to the formation of
desired product 7a and 7b in 84% and 75% yields respectively where PMB protected 7aʹ was
synthesized in 82% yield. The electronic features of the azole ring did not deter the efficiency of cross-
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Table 2. Optimization table for selective Suzuki-Miyaura arylation at C-5 position of 6aa
4
5
6
7
8
H3CO
OCH3
Catalyst
Ligand
Br
Cl
Cs2CO3 (2 equiv.)
+
+
N
Cl
N
Sovent
T°C,2 h
N
CH3
N
N
Cl
N
9
CH3
CH3
B(OH)2
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11
12
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7aa
6a
7a
Yield
(%)b
7a :7aa
Pd2dba3
(mol%)
dppf
(mol%)
T
(°C)
Entry
Solvent (v:v)
Toluene :Ethanol
(1:1)
Toluene :Ethanol
(1:1)
Toluene :Ethanol
(1:1)
Toluene :Ethanol
(3:1)
1,4-Dioxane : Water
(3:1)
1,4 Dioxane:Water
(6:1)
1,4-Dioxane : Water
(8:1)
1
2
5
10
10
20
20
20
20
20
60
37:47
5
80
33:59
20:39
20:13
31:0
3
10
10
10
10
10
100
100
100
100
100
4c
5d
6
84:0
7
46:0
aReaction conditions: 6a (0.05 g, .155 mmol), catalyst, ligand, 4-methoxy phenyl boronic acid (0.024 g,
0.155 mmol, 1 equiv.), Pd2dba3, dppf, Cs2CO3 (0.31 mmol, 2 equiv.), Solvent (2 mL, 0.077 M), T °C.
bIsolated yields of 7a and 7aa. cConv. = 38%. dConv. = 56%
coupling at the C-5 position as observed for 7c-d. Importantly introducing bicyclic naphthyl ring at C-5
gave the corresponding products 7f and 7g in 87% and 78% respectively. Triphenyl amine which act as
excellent hole transporting agent8e can be incorporated at 5th position in 60% yield (7h). Highly
conjugated and sterically hindered 1-pyrene was installed at 5th position in 68% yield (7i). The essential
feature of this step is highlighted by the two hetero-aryl coupling reactions seen for the products 7j and
7k, where 3-thiophene and 4-pyridyl groups are installed in a sequential manner in 67% and 66% yields
respectively.
A third SMC arylation was achieved at C-6 position of the sterically hindered azine of 3,5-
substituted di-aryl 7-azaindoles (7a-7i,7aʹ). Building on the conditions of C-5 SMC arylation, different
ligands were screened and solvent ratio was changed. The C-6 SMC arylation was achieved on 6-
chloro-5-(4-methoxyphenyl)-1-methyl-3-phenyl-1H-pyrrolo[2,3-b]pyridine (7a) with 4-methyl phenyl
boronic
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9
Scheme 4. Scope for selective C-5 arylation of mono-aryl 7-azaindoles, 6a
Pd2dba3 (10 mol %)
Ar1
Ar1
dppf (20 mol %)
Ar2 - B(OH)2 (1.0 equiv).
Cs2CO3 (2 equiv.)
Ar2
Br
Cl
N
Cl
N
N
Dioxane: water (6:1)
100°C, 2 h
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
39
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CH3
7a-i. 7a' b
CH3
6
F
CF3
H3CO
H3C
F3C
N
N
N
Cl
N
Cl
N
Cl
N
R
CH3
, 88 %
CH3
, 75 %
7a
R = Me, , 84 %
7c
7b
c CH3
7a
, 82 %
OCH3
R = PMB,
H3C
H3CO
N
N
N
Cl
N
Cl
N
Cl
N
CH3
CH3
CH3
, 74 %
7f
, 87 %
7d
7e
, 80 %
CH3
N
N
N
Cl
N
N
CH3
Cl
N
Cl
N
CH3
, 60%
CH3
7h
7i,
68%
7g
, 78 %
S
S
N
N
N
CH3
Cl
N
Cl
N
CH3
7k
, 66 %
7j
, 67 %
Reaction conditions: 5 (0.161 g, 0.5 mmol, 1 equiv.), Ar2-B(OH)2 (0.5 mmol, 1 equiv.), Pd2dba3 (0.05 mmol, 10 mol%), dppf (0.1 mmol,
20 mol%), Cs2CO3 (1 mmol, 2 equiv.), Dioxane: water (6:1, 5 mL), T = 100 °C, 2 h. Isolated yields of 7a-7i,7aʹ.c PMB = p-methoxy
b
benzyl.
acid (1.1 equiv.) using Pd2dba3 (10 mol%), SPhos (20 mol%), Cs2CO3 (2 equiv.) in 1,4-dioxane: water
(3:1 ratio, 2 mL) at 100 °C to yield 79% of 8a (Table 3). The crystal structure of 8a was confirmed by
X-ray crystallography (see Figure S5, Table S2 in ESI).
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7
The different aryl and hetero-aryl groups were integrated at the 6th position on the electron poor
azine of 7-azaindole in moderate to good yields (Scheme 5). The presence of electron donating and
electron withdrawing aryl substituent at C-5 position produced corresponding products 8a, N-PMB
8
9
Table 3. Optimization table for Suzuki-Miyaura arylation at C-6 position of 7aa
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53
54
55
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59
60
H3CO
Pd2dba3
Ligand
H3CO
CH3
Cs2CO3 (2 equiv.)
+
Solvent
100°C, 6 - 12 h
N
CH3
N
CH3
N
Cl
N
B(OH)2
8a
7a
H3C
Entry
Ligand
dppf
Solvent (v:v)
Yield (%)b
1c
2
1,4-Dioxane : Water (6 :1)
1,4-Dioxane : Water (6 :1)
n.r.
n.r.
dppf
3
4
5
XantPhos
PPh3
1,4-Dioxane : Water (6 :1)
1,4-Dioxane : Water (6 :1)
1,4-Dioxane : Water (3 :1)
14
n.r.
79
SPhos
aReaction conditions : 7a (0.05g, 0.143 mmol,1 equiv.), 4-methyl Phenyl boronic acid (0.021 g, 0.157
mmol,1.1 equiv.), Pd2dba3 (0.0143 mmol, 10 mol%), Ligand (0.0286 mmol, 20 mol %), Cs2CO3 (0.286 mmol,
2 equiv.), Solvent (2 mL, 0.072 M), 100 °C, 6- 12 h. Isolated yields of 8a,c5 mol% Pd2dba3 and 10 mol%
b
dppf.
protected 8aʹ and 8b in 79%, 66% and 43% yields respectively. The use of electron deficient 3,5-
bis(trifluoromethyl) substituted phenyl boronic acid as cross-coupling partner generated 8c in good
yields (68%) but bicyclic benzo[d][1,3]dioxole and naphthyl boronic acids procured the desired
products in 42-69% (8d-e). The feasibility of this reaction in substrates where C-5 position was
preinstalled with a 3-naphthyl substituent was examined and noted that 8f-h were synthesized in 55-
69% yield successfully. The compound 8i, having 3-thienyl, 4-pyridyl and 3-pyridyl groups was
obtained in moderate yield showing the robustness of sequential hetero-aryl coupling using this method.
Compound 8j is formed in moderate yield of 42% showing the C6 coupling of sterically hindered 1-
pyrene group.
Lastly, C-2 arylation of sterically crowded C-3, C-5, C-6 tri-aryl 7-azaindole was achieved
through C-H activation. Literature provides a number of methods for arylation of indoles14 with much
emphasis on C-2 arylations15 and role of silver salts has been elucidated.16 Pd(OAc)2 (5 mol%), 4-nitro
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benzoic acid (1.5 equiv.), AgOAc (1 equiv.) was used for C-C coupling between 4-iodoanisole (2
4
5
equiv.)
6
7
8
9
Scheme 5. Scope for synthesis of C-3, C-5, C-6 substituted tri-aryl 7-azaindoles a
Pd2dba3 (10 mol %)
Ar1
Ar1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SPhos (20 mol %)
Ar2
Ar2
Ar3 - B(OH)2 (1.1 equiv.)
Cs2CO3 (2 equiv.)
N
N
Dioxane:Water (3:1)
100°C
Ar3
N
Cl
N
CH3
8a-i,8a
b
CH3

7
6-12 hrs
F
CF3
H3CO
H3C
F3C
F3C
N
N
N
N
N
N
8b
R
CH3
, 68 %
CH3
8c
H3C
, 43 %
H3C
H3C
=
8a
Me, , 79 %
R
CF3
c
8a
R = PMB, , 66 %
CH3
OCH3
CH3
H3CO
N
N
N
N
N
N
CH3
, 42 %
CH3
, 66 %
CH3
, 69 %
8d
8e
8f
O
O
OCH3
S
N
H3CO
H3CO
N
N
CH3
, 42 %
N
N
N
N
CH3
, 67 %
CH3
, 55 %
8g
N
8h
O
8i
OCH3
O
H3CO
N
CH3
N
8j
, 42%
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aReaction conditions: 7 (0.105 g, 0.3 mmol,1 equiv.), Ar3-B(OH)2 (0.33 mmol, 1.1 equiv.), Pd2dba3 (0.03 mmol, 10 mol%), SPhos (0.06
mmol, 20 mol%), Cs2CO3 (0.6 mmol, 2 equiv.) in 5 mL 1,4-Dioxane: Water (3:1), 100 °C, 6 -12 h. bIsolated yields of 8a-8i, 8aʹ.c PMB =
p-methoxy benzyl group.
7
8
9
and 1 equiv. of 8a. The reaction mixture was stirred in dry DMF at 120°C under N2 atm. but no
reactant conversion took place (Table 4, entry 1). Increased catalyst load did not work (entry 2)
but changing the silver salt to silver oxide gave 9a in 14% yield, showing 66% conversion of 8a
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Table 4. Optimization table for C-2 arylation of 8a a
Pd(OAc)2
o-nitro benzoic acid
H3CO
H3CO
Ag additive
4-iodoanisole
Cs2CO3
OCH3
dry DMF
N2 atmosphere
120°C, 12 h
N
N
N
N
CH3
CH3
H3C
9a
8a
H3C
R-Ph-
Pd(OAc)2
(mol%)
Ag
additive
Base
(5 mol%)
Conv.
(%)
Yieldb
(%)
Entry
COOH
(R = )
4-NO2
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
1
2
5
AgOAc
AgOAc
Ag2O
Ag2O
Ag2O
AgOTf
AgOTf
AgOTf
AgOTf
-
-
-
-
-
-
-
-
66
-
61
80
>90
>90
>90
n.r
n.r.
14
n.r.
17
65
70
21
75
10
10
10
10
10
10
10
10
3c
4d
5
6
7
Cs2CO3
Cs2CO3
Cs2CO3
8e
9f
aReaction conditions: 8a (0.05 g, 0.125 mmol), 4-iodoanisole, Pd(OAc)2, Ag additive (1 equiv.), nitrobenzoic acid (0.1875
mmol, 1.5 equiv.), Cs2CO3, DMF (2 mL, 0.062 M)), T, 12 h, N2 atmosphere. Isolated yields of 9a. 32 h. PPh3 (5
mol%), 2 equiv. iodoanisole.eT = 80 °C. f 1.5 equiv. iodoanisole
b
c
d
(entry 3) in 32 h. PPh3 was added as ligand to increase the yield of 9a but the substrate
remained unchanged (entry 4). A comparatively more electron deficient, 2-nitro benzoic acid
was used and a slight increase in the yield of the product (17%, Conversion: 61%, entry 5) was
observed. Electron poor AgOTf was utilized in further experiments instead of Ag2O to get 80%
conversion of 8a leading to an enhanced 65% yield of 9a (entry 6 ). Surprisingly, addition of
catalytic amount of Cs2CO3 further increased the yield of the 9a to 70% and Conv. > 90% (entry
7). However, decreasing the temperature also decreased the yield (21%, entry 8) suggesting
importance of temperature in C-2 arylation of 8a. We noticed that decreasing the amount of 4-
iodo anisole was advantageous to the reaction where 75% yield of 9a is recorded along with
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conversion > 90% (entry 9). The crystal structure of 9a was confirmed by X-ray crystallography
4
5
(see Figure S6, Table S3 in Supporting information).
6
7
8
Scheme 6. Scope for synthesis of tetra-aryl 7-azaindoles. a
9
Ar1
Ar1
Pd(OAc)2 (10 mol %)
2-nitrobenzoic acid (1.5 equiv.)
AgOTf (1 equiv.)
10
11
12
13
14
15
16
17
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60
Ar2
Ar3
Ar2
Ar3
I
Ar4
Cs2CO3 (5 mol %)
+
Ar4
N
N
N
N
dry DMF,120°C
6-12 hrs
CH3
CH3
9a-f
Conv. > 90 %
8
N2 atm
H3CO
OCH3
F
N
N
N
N
CH3
CH3
H3C
H3C
O
b
b
9c
, 66% (23%)
CH3
b
9b
, 48% (24%) , Conv.>80 %
OCH3
O
9a
, 75% (37%)
OCH3
H3C
F
F
N
N
N
N
N
N
CH3
CH3
CH3
c
d
b
c
b
b
9f
, 54% (19%)
9e
, 95% (35%)
9d
, 53% (20%)
OCH3
aReaction conditions : 8 (0.05 g, 0.125 mmol, 1 equiv), Ar4-I (0.1875 mmol, 1.5 equiv.), Pd (OAc)2 (0.0125 mmol, 10 mol%),
AgOTf (0.125 mmol, 1 equiv.), 2- nitro benzoic acid (0.1875 mmol, 1.5 equiv.), Cs2CO3 (0.00625 mmol, 5 mol%), DMF (2 mL,
0.062 M)), T = 120 °C, 6-12 h, N2 atmosphere. b Overall Yields (4 steps). c Second addition of Ar4-I (1.5 equiv.) and Pd(OAc)2
(10 mol%). d Second addition of 1-Fluoro-4-iodobenzene (1.5 equiv).
The synthetic elaboration of methodology was done to get different tetra-arylated
products (Scheme 6). Electron donating aryl iodides gave respective tetra-aryl products in good
yields as seen for 9a (75%) and sterically crowded 9c (66%). On the contrary the electronically
poor 1- fluoro-4-iodobenzene yielded corresponding product (9b) in 48% yield with conversion
> 80%. We hoped changing the electronic character of C-3 substituted azole ring would help in
increasing the efficiency for arylation at C-2 position, as observed in 9d-9f. A second addition
of Pd(OAc)2 (10 mol%) and corresponding iodo-arene (1.5 equiv.) was required to drive the
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reaction to completion resulting in 9d (53%) and 9e (95%). Compound 9f was synthesized in
54% yield in the presence of an additional 1.5 equiv. of 1-fluoro-4-iodobenzene.
The above methodology was used for large scale synthesis of tetra-aryl 7-azaindole 9a on
> 0.5 mmol scale (Scheme 7). 6a was produced in 51% yield from 2.7 mmol of 5. 7a was
synthesized in 78% yield from 1.37 mmol of 7a and 8a was procured in 79% yield from 1.1
mmol of 7a. Finally tetra-aryl 7-azaindole was synthesized in 69% yield from 0.85 mmol 8a
with the overall yield of 9a being 22%.
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Scheme 7: Large scale synthesis of 9a
H3CO
I
6a
, 51%, 1.37 mmol
7a
Br
Cl
, 78%, 1.06 mmol
8a
OCH3
N
N
N
N
, 79%, 0.86 mmol
H3C
CH3
, 2.7 mmol
Amount = 1g
CH3
9a
5
, 69%, 0.59 mmol
Amount = 300 mg
Overall Yield = 22%
3. OPTICAL PROPERTIES
The optical properties of synthesized multi-aryl 7-azaindoles (6a, 7a, 8a, 9a-9f) were studied in
THF using UV-Visible and fluorescence spectroscopy (Table S1, Figure S1 in Supporting information,
Table 5). The UV-Vis absorption spectra of six tetra-aryl compounds (9a-f) used for the study exhibit
absorption bands in the range of 265-279 nm due to π→π* transitions and a broad shoulder peak centred
~ 330 nm is attributed to intramolecular charge transfer (ICT) transitions in 7-azaindoles and due to
donor methoxy substituted aryls and acceptor 7-azaindole core. 17
Table 5. Spectroscopic profile for 9a-9f
Stokes
shift
nm
λ max abs (π →π* ) λ abs (shoulder peak) λ em max
Molar absorption
Compound
nm
nm
nm
coefficient (Lmol-1cm-1)
9a
9b
9c
9d
9e
9f
272
265
269
279
279
268
332
333
334
332
332
331
423
423
429
457
462
437
151
158
160
178
183
169
25,309
68,554
62,995
90,993
48,426
54,873
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The absorption maxima did not show much variation for the six tetra-aryl compounds but a distinct red
5
6
7
shift in wavelength was observed in emission maxima for 9d and 9e where substitution by naphthalene
8
9
10
11
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13
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60
A
B
Figure 2. A) Normalized absorption spectra and B) normalized emission spectra for 9a-f
ring at C-6 position shifted the emission wavelength to 457 (Stokes Shift, Δλ = 178 nm) and 462 nm
(Stokes Shift, Δλ = 183 nm) respectively (Figure 2).
Intrigued by the structural diversity of the synthesized multi-aryl derivatives and considering 7-
azaindole as the molecular rotor, its aggregate induced emission (AIE) characteristics in THF/water
were studied as these tetra-aryl derivatives were not soluble in water. First, the effect of arylation on
aggregate induced emission was studied for 6a, 7a, 8a and 9a to validate the effect of arylation on AIE
properties (see Figure S1 (C) and (D) in Supporting information). Mono-aryl and di-aryl 7-azaindoles
showed quenching of fluorescence upon increase of water fraction whereas tri-aryl derivative, 8a and
tetra-aryl 9a showed aggregate induced emission. The emission intensity for 8a was observed to be very
low compared to 9a at 70% water fraction. Compounds 9a-f showed a marked and gradual increase in
fluorescence intensity which was observed as the fraction of water (v/v %) in THF/water is increased
for all six tetra-aryl compounds (see Figure S1 in Supporting information). The ~13-fold increase in
emission is observed for 9e at 90% water fraction and is highest when compared to other derivatives
(Figure 3). The aggregate formation was corroborated by DLS (Dynamic Light Scattering)
measurements where aggregate size equals 106 nm (see Figure S2 in Supporting information). At 95%
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water fraction, fluorescence intensity (I/Io) is substantially decreased (I is fluorescence intensity of 9a-
9f in pure THF and THF/water fractions and I0 is the fluorescence intensity of 9a-9f in pure THF).
6
7
8
9
B
A
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60
Figure 3. A) Plot of ratio of maximum fluorescence intensity (I/Io) of 9a-9f in THF vs. Fraction of
water. B) Variation of emission intensity with increasing water fraction in THF (Concentration: 10-6 M,
λex = 280 nm.).
Further, at 99% we see quenching in fluorescence emission (see Figure S1(B) and S1(D) in Supporting
information). The relative quantum yield determined for 9e in THF and THF/ Water (1:9) was found to
be 0.16 and 0.31 respectively (see Figure S3 in Supporting information).
The presence of naphthalene substituent at C-6 position (9d and 9e) shows an increased intensity
as compared to other compounds at 90% water fraction suggesting that a highly conjugated ring at C-6
can positively affect the emissive profiles of tetra-aryl 7-azaindoles in aqueous THF. Naphthyl ring at
C-5 position did not show such red shift and enhanced emission in AIE emission. Similarly, presence of
electron withdrawing 4-fluoro phenyl group at C-2 position (9b) has shown an increase in aggregation
induced fluorescence intensity as compared to its electron-donating counterpart (9a). AIE mechanism
was understood by studying the packing of crystal structure of 9a. The twisted conformation of aryl
groups showed torsional angles as 52.4°, 55.6°, 62.2°, 40.5°. No π-π stacking was noted but edge to face
weak interactions were prominent. CH···π centre intermolecular interaction between methoxy
hydrogens on C-5 aryl and C-3 aryl is observed with a short distance of ~2.52 Å. Various other
intermolecular interactions are noted between azine N and C-H (C-3 aryl) as well as C-H (C-5 aryl)/ O
atom of methoxy on C-2 aryl (Figure 4). Such weak interactions of aryls and substituents may have
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rendered the molecule rigid causing restricted rotation of aryl groups.18 Presence of hydrogen donating
substituent on the aryl ring is therefore seen to aid in the enhancement of aggregate induced emission.
6
7
8
9
10
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Figure 4. Crystal packing in order to show the various intermolecular interactions (shown in blue).
4. CONCLUSION
In conclusion using novel tri-halogenated 7-azaindole 5, we strived towards sequential and
selective synthesis of C-2, C-3, C-5, C-6 substituted tetra-aryl derivatives. The structural enhancements
were done using three selective intermolecular Pd catalyzed Suzuki-Miyaura C-C cross-coupling on C-
3, C-5, C-6 and lastly via AgOTf driven Pd catalyzed C-2 arylation. The essential feature of this
sequential method is the stability of this reaction to three subsequent arylations, accommodating hetero-
aryls and bulky substituents. C-H arylation on a sterically hindered C-2 positions have also been
reported. The tri-aryl and tetra-aryl derivatives were synthesized in moderate to excellent yields and 9a-
f are observed to show an enhanced fluorescence emission profile in state of aggregation. This study
provides access to synthesize such 7-azaindole derivatives as prospects for material sciences where such
extensive conjugation to a ring provides a lever to manipulate a molecule’s optoelectronic and photo-
physical properties. This work is part of ongoing research in our lab on 7-azaindole derived AIEgens.
5. EXPERIMENTAL SECTION
General Information:
Unless otherwise noted, all reagents were purchased from commercial suppliers and used
without purification. All Suzuki-Miyaura reactions were performed in round bottom flask and
monitored through thin layer chromatography (TLC silica gel F254, glass plates) and analysed using 254
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nm UV light and Iodine, ninhydrin stains. C-2 arylation was performed in a sealed tube under N2
atmosphere. Melting points were recorded on Büchi Melting Point B-545 instrument and are
uncorrected. Organic solutions were concentrated by rotary evaporation on BUCHI-Switzerland; R-210
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rotary evaporator and vacuum pump V-700. H and C NMR spectra were recorded with BRUKER
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500 and Jeol 400 MHz NMR instrument. H NMR and proton decoupled 13C NMR spectra were
recorded with a 400 MHz (1H= 400 MHz and 13C = 101 MHz) or 500 MHz (1H = 500 MHz and 13C =
126 MHz) spectrometer. Chemical shifts value of 1H NMR were recorded in parts per million (ppm, δ)
relative to tetramethylsilane (TMS, 0.00 ppm) calibrated to the residual peak as an internal standard
(CDCl3: δ =7.26 ppm and DMSO: δ= 2.50ppm). Data are written as: Chemical shifts as part per million
(ppm, δ), multiplicity (s= singlet, d= doublet, t= triplet, q = quartet, m = multiplet), coupling constants
(J) were reported in Hertz (Hz) and integration value. Chemical shifts value of proton decoupled
13C{1H} NMR were recorded in parts per million (ppm, δ) and calibrated to the residual peak as an
internal standard (CDCl3: δ = 77.0 ppm and DMSO: δ= 39.0 ppm). Mass spectra were recorded with
Waters SYNAPT G2 with 2D nano ACQUITY System and Agilent LCMS with Quadropole time of
flight. UV-Visible spectra were recorded in Cary 300 UV-Vis spectrophotometer and Emission spectra
were recorded in Cary eclipse fluorescence spectrophotometer. Relative quantum yield for 9e was
measured using 0.1 M Quinine sulphate in H2SO4 as a standard. X-ray reflections were collected on
Bruker D8 Quest diffractometer with CMOS detector using MoKα radiation, generated from the micro-
focus sealed tube. Cell determination, data collection and data reduction were performed with the help
of Bruker APEX2 (version: 2.1-b24) software. Compound 2 and 3 were synthesized by reported
procedure in literature.19. 20
5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine 7-oxide (3). In a round bottom flask containing a
solution of 2 (10 g, 30.97 mmol, 1 equiv.) in Diethyl ether (100 mL) was added 77% m-
chloroperbenzoic acid (77.42 mmol, 13.36 g, 2.5 equiv.) portion wise. The mixture was stirred at room
temperature for 1 hour as white precipitate is observed. The reaction was checked for completion using
TLC and filtered. The white solid obtained was then dried and added to 200 mL distilled water and to it
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saturated solution of potassium carbonate was added till the solution attained a pH of 9-10. The mixture
was stirred overnight, filtered and dried. Off-white solid was obtained by filtration and washed with
cold distilled water (50 mL) which was used without purification; Off-white solid (3, 9.13 g, 87%); m p:
decompose > 250°C; 1H NMR (500 MHz, DMSO-d6) δ 13.14 (br, 1H), 8.50 (s, 1H), 7.75 (s, 1H), 7.55
(s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 138.0, 133.3, 132.7, 127.0, 122.8, 109.0, 56.5. HRMS
(ESI) m/z calculated for C7H5BrIN2O [M+H]+ 338.8630, found. 338.8641.
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Synthesis of 5-Bromo-6-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (4). 4 was synthesized by a
known method in literature.21 To a dry round bottom flask containing a magnetic bead was added 5-
bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine 7-oxide (3,169 mg, 0.5 mmol, 1 equiv.) in dry THF. The
solution was purged with N2 and inert atmosphere was maintained during the reaction. HMDS (1 equiv.)
was added followed by slow addition of trichloroacetyl chloride (2.5 equiv.) with constant stirring on an
ice bath. After addition the reaction was stirred at room temperature for 1 h and monitored using TLC.
On completion THF was evaporated and mixture was extracted using ethyl acetate and washed with
saturated solution of sodium bicarbonate. The organic layer was dried using anhydrous sodium sulphate
and evaporated. The residue was purified using column chromatography on silica gel (Ethyl acetate:
Hexanes (30: 70)) to obtain a white solid (4, 1,404 mg, 42%); mp : decompose > 260 ºC; 1H NMR (500
MHz, DMSO-d6) δ 12.51 (br, 1H), 8.06 (s, 1H), 7.85 (s, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ
145.9, 142.9, 134.2, 133.6, 123.6,110.2, 54.2. HRMS (ESI) m/z calculated for C7H4BrClIN2 [M+H]+
356.8291, found 356.8300.
Synthesis of 5-Bromo-6-chloro-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (5).
5
was
synthesized by known methods in literature.3e 5-bromo-6-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (4,
357 mg, 1 mmol, 1 equiv.) was taken in DMF in a round bottom flask. NaH (1 equiv.) was added to it
portion wise at 0ºC - 5ºC and stirred for 30 min under N2 atmosphere. Methyl iodide (1.1 equiv.) was
then added to it and stirred for 3 hours. On completion of reaction as observed in TLC, ethyl acetate was
added to the reaction mixture. The organic layer was washed with water and brine followed by drying
using anhydrous sodium sulphate. Organic layer was evaporated and compound was purified using
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column chromatography (Ethyl acetate: Hexanes (2: 98)) to give white product (5, 252 mg, 68%); mp:
174.5-175.6 °C; 1H NMR (CDCl3, 500 MHz) δ 7.94 (s, 1H), 7.27 (s, 1H), 3.85 (s, 3H). 13C{1H} NMR
(CDCl3, 126 MHz) δ 145.1, 144.3, 134.7, 134. 6, 123.5, 111.1, 51. 7, 31.9. HRMS (ESI) m/z calculated
for C8H6BrClIN2 [M+H]+ 370.8447, found 370.8429
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Synthesis of 5-Bromo-6-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine (5ʹ). 5ʹ
was synthesized by known method in literature.22 A round-bottom flask containing a magnetic bead was
charged with 5-bromo-6-chloro-3-iodo-1H-pyrrolo [2,3-b]pyridine (4, 357 mg, 1 mmol, 1 equiv.) in
DMF (10 mL), 3 equiv. of K2CO3 and p-methoxybenzyl chloride (1.2 equiv.). The reaction was stirred
at room temperature for 6 hours under N2 atmosphere. On completion of reaction, ethyl acetate (50 mL)
was added and washed thrice with 50 mL distilled water and 50 mL brine solution. The organic layer
was evaporated and purified using column chromatography (Ethyl acetate: hexanes (0.5:99.5)). The
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product was obtained as white solid (5ʹ, 253 mg, 53%); mp: 146.0-147.3 °C, H NMR (CDCl3, 500
MHz) δ 7.92 (s, 1H), 7.20-7.19 (m, 3H), 6.85 (d, 2H, J = 8.5 Hz), 5.31 (s, 2H), 3.78 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 159.5, 144.8, 144.4, 134.6, 133.3, 129.6, 128.1, 123.5, 114.3, 111.3, 55.3,
52.5, 48.0.
General Procedure for synthesis of 6a-6k. In a round bottom flask equipped with a magnetic
stirrer was added 5 (1 equiv., 0.5 mmol), Ar1-B(OH)2 (1 equiv.), Pd2dba3 (5 mol%), dppf (5 mol%),
Cs2CO3 (2 equiv.) in toluene: ethanol (1:1, 5 mL). The reaction mixture was stirred in an oil bath at 60
°C for 15 min and the mixture was filtered through a bed of Celite. The filtrate was then evaporated
using rotatory evaporator and purified through column chromatography on silica gel using ethyl acetate:
hexanes solvent mixture. The purified compounds (6a-6k) were obtained in 40 - 70% yields. ( Note:
Mass of 6i was found by MALDI as HRMS could not yield the mass of this compound)
5-Bromo-6-chloro-1-methyl-3-phenyl-1H-pyrrolo[2,3-b]pyridine (6a), 119 mg, 74%; white
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solid; mp.: 109-110 °C; H NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.54 (d, 2H, J = 7.7 Hz), 7.45 (t,
2H, J = 7.4 Hz), 7.35 (s, 1H), 7.32 (t, 1H, J = 7.3 Hz), 3.88 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
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146.0, 143.2, 133.8, 133.4, 129.1, 127.6, 126.9, 126.7, 119.0, 114.9, 110.5, 31.7; HRMS (ESI) m/z
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calculated for C14H11BrClN2 [M+H]+ 320.9794, found 320.9814.
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solid; mp: 130-131°C; H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 7.43 (d, 2H, J = 7.8 Hz), 7.31 (s,
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1H), 7.25 (d, 2H, J = 7.6 Hz), 3.87 (s, 3H), 2.40 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ 146.0,
143.1, 136.5, 133.4, 130.8, 129.8, 127.3, 126.8, 119.0, 114.9, 110.4, 31.6, 21.2; HRMS (ESI) m/z
calculated for C15H13BrClN2 [M+H]+ 334.9950, found 334.9935 .
5-Bromo-6-chloro-3-(4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (6c), 123 mg, 70%
; white solid; mp: 134.2-136.0 °C; 1H NMR (CDCl3, 500 MHz) δ 8.28 (s, 1H), 7.41 (d, 2H, J=8.5 Hz),
7.23 (s, 1H), 6.97 (d, 2H, J = 8.7 Hz), 3.84 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ
158.5, 145.9, 143.0, 133.3, 128.0, 127.0, 126.2, 119.0, 114.6, 114.5, 110.2, 55.4, 31.6; HRMS (ESI) m/z
calculated for C15H13BrClN2O [M+H]+ 350.9900 found 350.9879.
5-Bromo-6-chloro-3-(3-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (6d) ; 70 mg, 40%;
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white solid : mp: 126-127 °C; H NMR (CDCl3, 500 MHz) δ 8.36 (s, 1H), 7.37-7.34 (m, 2H), 7.11 (d,
1H, J = 7.7 Hz), 7.05 (d, 1H, J = 1.9 Hz), 6.85 (dd, 1H, J= 8.2 Hz, 2.2 Hz), 3.87 (s, 6H) ; 13C{1H}
NMR (CDCl3, 126 MHz) δ160.1, 146.0, 143.2, 135.1, 133.4, 130.1, 127.8, 119.4, 118.9, 114.7, 112.9,
111.7, 110.5, 55.4, 31.7; HRMS (ESI) m/z calculated for C15H13BrClN2O [M+H]+ 350.9900, found
350.9882 .
5-Bromo-6-chloro-3-(4-fluorophenyl)-1-methyl-1H-pyrrolo [2,3-b]pyridine (6e); 110 mg, 65%;
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white solid; mp: 150-151 °C; H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.54-7.46 (m, 2H), 7.31 (s,
1H), 7.16-7.12 (m, 2H, J= 8.2 Hz), 3.89 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 161.8 (d, 1C, J =
246.1 Hz), 145.9, 143.4, 133.2, 129.8 (d, 1C, J = 3.3 Hz), 128.5 (d, 1C, J = 7.9 Hz), 127.5, 118.9, 116.0
(d, 1C, J = 21.5 Hz), 114.0, 110.6, 31.6; HRMS (ESI) m/z calculated for C14H10BrClFN2 [M+H]+
338.9700, found 338.9721.
5-Bromo-6-chloro-1-methyl-3-(naphthalen-2-yl)-1H-pyrrolo [2,3-b]pyridine (6f); 94.7 mg,
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51%; white solid; mp: 150.7-151.4 °C; H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 7.94 (s, 1H), 7.88
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(d, 1H, J = 8.5 Hz), 7.85-7.83 (m, 2H), 7.63 (dd,1H, J = 8.4 Hz, 1.6 Hz), 7.51-7.45 (m, 2H), 7.42 (s,
1H), 3.88 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 146.1, 143.3, 133.8, 133.5, 132.2, 131.2, 128.8,
128.0, 127.8, 127.8, 126.5, 125.8,125.4, 124.9, 119.0, 114.8, 110.6, 31.7; HRMS (ESI) m/z calculated
for C18H13BrClN2 [M+H]+ 370.9950, found 370.9960.
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3-(Benzo[d][1,3]dioxol-5-yl)-5-bromo-6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (6g); 115.1
mg 63% ; white solid; mp: 131.1-132.6 °C; 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.27 (s, 1H),
7.00 (m, 2H), 6.92-6.90 (m, 1H), 6.02 (s, 2H ), 3.88 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 148.3,
146.6, 145.9, 143.3, 133.3, 127.7, 127.2, 120.4, 119.0, 114.8, 110.4, 109.00, 107.6, 101.2, 31.6; HRMS
(ESI) m/z calculated for C15H11BrClN2O2 [M+H]+ 364.9692, found 364.9706 .
5-Bromo-6-chloro-1-methyl-3-(naphthalen-1-yl)-1H-pyrrolo[2,3-b]pyridine (6h); 128 mg, 69%;
white solid; mp: 145.4-147.1 °C ; 1H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.93 (t, 2H, J = 8.9 Hz),
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7.87 (d, 1H, J = 8.1 Hz), 7.54-7.47 (m, 3H), 7.45-7.42 (m, 1H), 7.34 (s, 1H), 3.94 (s, 3H); C{1H}
NMR (126 MHz, CDCl3) δ 145.6, 143.4, 134.0, 133.7, 132.1, 131.0, 129.6, 128.6, 127.9, 127.8, 126.3,
126.1, 125.7, 125.6, 120.9, 113.3, 110.4, 31.7; HRMS (ESI) m/z calculated for C18H13BrClN2 [M+H]+
370.9951, found 370.9971 .
5-Bromo-6-chloro-1-methyl-3-(pyren-1-yl)-1H-pyrrolo[2,3-b]pyridine (6i); 100.6 mg, 45%;
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white solid; mp: 227.3-228.4 °C; H NMR (500 MHz, CDCl3) δ 8.21-8.18 (m, 3H), 8.17 (s, 1H), 8.09
(s, 2H), 8.04-7.98 (m, 4H), 7.44 (s, 1H), 3.98 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 145.8, 143.5,
133.8, 131.5, 131.0, 130.7, 129.9, 129.2, 128.4, 128.1, 127.7, 127.6, 127.4, 126.2, 125.3, 125.2, 125.0,
125.0, 124.9, 124.9, 121.0, 113.8, 110.6, 31.8. Exact mass calculated for C24H14BrClN2 444.0029,
found. 444.0056.
5-Bromo-6-chloro-1-methyl-3-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (6j); 114.6 mg, 70%;
white solid; mp; 152.8-153.7 °C; 1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.42 (dd, 1H, J = 4.8 Hz,
2.9 Hz), 7.34 (d, 1H, J = 1.7 Hz), 7.33 (s, 1H), 7.29 (d, 1H, J = 4.9 Hz), 3.86 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 145.8, 143.3, 134.1, 133., 127.5, 126.4, 126.3, 119.1, 118.9, 110.4, 110.3, 31.6;
HRMS (ESI) m/z calculated for C12H9BrClN2S [M+H]+ 326.9358, found 326.9334.
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3-(5-Bromo-6-chloro-1-methyl-1H-pyrrolo [2,3-b]pyridin-3-yl)benzaldehyde (6k); 69.9 mg, 40%; white
solid; mp: 169.8-170.9 °C; 1H NMR (500 MHz, CDCl3) δ 10.11 (s, 1H), 8.39 (d, 1H, J = 2.0 Hz), 8.08
(s, 1H), 8.05 (d, 1H, J = 2.0 Hz), 7.87 (d, 1H, J = 7.6 Hz), 7.84 (d, 1H, J = 7.7 Hz), 7.66 (t, 1H, J = 7.6
Hz), 3.91 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 192.1, 145.0, 144.1, 136.9, 134.7, 133.0, 129.8,
129.6, 128.6, 128.4, 126.4, 120.00, 113.0, 109.7, 29.0; HRMS (ESI) m/z calculated for C15H11BrClN2O
[M+H]+ 348.9743, found 348.9756.
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Synthesis of 5-Bromo-6-chloro-1-(4-methoxybenzyl)-3-phenyl-1H-pyrrolo[2,3-b]pyridine (6aʹ)
In a round bottom flask equipped with a magnetic stirrer was added 5ʹ (1 equiv., 0.5 mmol), Ar1-
B(OH)2 (1 equiv.), Pd2dba3 (5 mol%), dppf (5 mol%), Cs2CO3 (2 equiv.) in Toluene: Ethanol (1:1,
5mL) . The reaction mixture was stirred at room temperature for 15 min and the mixture was filtered
through bed of celite. The filtrate was then evaporated using rotatory evaporator and purified through
column chromatography (Ethyl acetate: Hexanes (0.5: 99.5)) to give white solid (6aʹ, 113.2 mg, 53% );
mp: 116.6-117.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 7.50 (d, 2H, J = 7.7 Hz), 7.41 (t, 2H, J
= 7.5 Hz), 7.29-7.27 (m, 2H), 7.25-7.22 (m, 2H), 6.86 (d, 2H, J = 8.3 Hz), 5.37 (s, 2H), 3.78 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 159.5, 145.9, 143.4, 133.8, 133.5, 129.4, 129.0, 128.6, 126.9,
126.7, 126.1, 119.0, 115.5, 114.3, 110.7, 55.3, 47.8; HRMS (ESI) m/z calculated for C21H17BrClN2O
[M+H]+ 427.0213, found. 427.0224
General Procedure for synthesis of 7a-7i. In a round bottom flask equipped with a magnetic
stirrer was added 6 (1 equiv., 0.5 mmol), Ar2-B(OH)2 (1.0 equiv.), Pd2dba3 (10 mol%), dppf (20 mol%),
Cs2CO3 (2 equiv.) in Dioxane: Water (6:1, 5mL). The reaction mixture was stirred in an oil bath at 100
°C for 2 h. The reaction was cooled down to room temperature and ethyl acetate was added to it. The
organic layer was washed with water followed by brine solution and dried with anhydrous sodium
sulphate. The organic layer was then evaporated using rotatory evaporator and purified through column
chromatography (Ethyl acetate: Hexanes). The purified compounds (7a-7i) were obtained in 66 – 84 %.
6-Chloro-5-(4-methoxyphenyl)-1-methyl-3-phenyl-1H-pyrrolo[2,3-b]pyridine (7a), Compound
was prepared from 6a;146.6 mg, 84%; white solid; mp: 128.2-128.7 °C; 1H NMR (500 MHz, CDCl3) δ
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8.14 (s, 1H), 7.59 (d, 2H, J = 7.6 Hz), 7.44-7.40 (m, 4H), 7.38 (s, 1H), 7.28 (t, 1H, J = 7.3 Hz), 6.99 (d,
2H, J = 8.4 Hz), 3.95 (s, 3H), 3.87 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 159.1, 146.6, 143.6,
134.4, 131.7, 131.4, 131.1, 129.0, 128.7, 126.9, 126.8, 126.4, 117.7, 115.4, 113.6, 55.3, 31.6; HRMS
(ESI) m/z calculated for C21H18ClN2O [M+H]+ 349.1107, found 349.1125.
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Compound was synthesized from 6a; 170.7 mg, 75%; white solid; mp: 148.0-149.0 °C; H NMR (500
MHz, CDCl3) δ 8.13 (s, 1H), 7.94 (s, 2H), 7.92 (s, 1H), 7.58 (d, 2H,J = 7.8 Hz), 7.47-7.43 (m, 3H), 7.31
(t, 1H, J = 7.4 Hz), 3.97 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 147.2, 142.7, 141.4, 133.9, 131.6
(q, 2C, J = 33.4 Hz), 131.2, 130.3 (d, 2C, J = 2.2 Hz), 129.1, 127.5, 127.0, 126.8, 126.0, 123.3 (d, 2C, J
= 272.8 Hz), 121.5-121.4 (m, 1C), 117.8, 115.9, 31.7; HRMS (ESI) m/z calculated for C22H14ClF6N2
[M+H]+ 455.0749, found 455.0737.
6-Chloro-3-(4-fluorophenyl)-1-methyl-5-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (7c); Compound
1
was synthesized from 6e; 154.3 mg, 88%; yellow semi-solid; H NMR (500 MHz, CDCl3) δ 8.07 (s,
1H), 7.54-7.51 (m, 2H), 7.37 (d, 2H, J = 8.0 Hz), 7.32 (s, 1H), 7.26 (d, 2H, J = 7.9 Hz), 7.10 (t, 2H, J =
8.7 Hz), 3.94 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 161.65 (d, 1C, J = 245.7 Hz),
146.57, 143.60, 137.45, 136.35, 131.19, 130.43 (d, 1C, J = 3.2 Hz), 129.9, 129.0, 128.9, 128.4 (d, 1C, J
= 7.7 Hz), 126.6, 117.6, 115.9 (d, 1C, J = 21.3 Hz), 114.5, 31.6, 21.3; HRMS (ESI) m/z calculated for
C21H17ClFN2 [M+H]+ 351.1064, found 351.1084.
6-Chloro-5-(4-methoxyphenyl)-1-methyl-3-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (7d); Compound
1
was synthesized from 6b; 134.6 mg, 74%; white solid; mp: 119.1-120.3 °C; H NMR (500 MHz,
CDCl3) δ 8.11 (s,1H), 7.48 (d, 2H, J = 7.9 Hz), 7.41 (d, 2H, J = 8.6 Hz), 7.33 (s, 1H), 7.22 (d, 2H, J=7.8
Hz), 6.98 (d, 2H, J = 8.6 Hz), 3.92 (s, 3H), 3.86 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3)
δ 159.1, 146.6, 143.5, 136.1, 131.7, 131.4, 131.2, 129.7, 128.5, 126.8, 126.5, 117.7, 115.3, 113.6, 55.4,
31.6, 21.2; HRMS (ESI) m/z calculated for C22H20ClN2O [M+H]+ 363.1264, found 363.1259 .
6-Chloro-3-(4-methoxyphenyl)-1-methyl-5-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (7e); Compound
1
was synthesized from 6c; 145.3 mg, 80%; white solid; mp; 113.6-113.8 °C; H NMR ( 500 MHz,
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CDCl3) δ 8.09 (s, 1H), 7.49 (d, 2H, J = 8.6 Hz), 7.38 (d, 2H, J = 7.8 Hz), 7.28-7.25 (m, 3H), 6.95 (d,
2H, J = 8.6 Hz), 3.92 (s, 3H), 3.83 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 158.4,
146.6, 143.3, 137.3, 136.5, 131.4, 129. 9, 128.9, 128.7, 128.1, 126.9, 126.2, 117.7, 115.1, 114.5, 55.4,
31.6, 21.3; HRMS (ESI) m/z calculated for C22H20ClN2O [M+H]+ 363.1264 found 363.1253 .
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6-Chloro-1-methyl-5-(naphthalen-2-yl)-3-phenyl-1H-pyrrolo[2,3-b]pyridine (7f); Compound
1
was synthesized from 6a; 160.7 mg, 87%; white solid; mp 210.4-211.6 °C; H NMR (500 MHz,
CDCl3) δ 8.25 (s,1H), 7.92-7.88 (m, 4H), 7.65 (d, 1H, J = 8.5 Hz), 7.61 (d, 2H, J = 7.7 Hz), 7.52 (dd,
2H, J = 5.9 Hz. 3.0 Hz), 7.44-7.41 (m, 3H), 7.28 (t,1H, J = 7.3 Hz), 3.97 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3)δ 146.8, 143.5, 136.9, 134.4, 133.2, 132.6, 131.7, 129.0, 128.8, 128.2, 128.1, 127.7, 127.5,
126.9, 126.9, 126.5, 126.3, 126.3, 117.7, 115.6, 31.6; HRMS (ESI) m/z calculated for C24H18ClN2
[M+H]+ 369.1158, found 369.1152 .
6-Chloro-1-methyl-5-(naphthalen-2-yl)-3-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (7g); Compound
1
was synthesized from 6b; 149.4 mg, 78%; white solid; mp: 165.1-166.6 °C; H NMR (500 MHz,
CDCl3) δ 8.23 (s, 1H), 7.92-7.88 (m, 4H), 7.65 (dd, 1H, J = 8.5 Hz, 1.4 Hz), 7.51-7.49 (m, 4H), 7.37 (s,
1H), 7.23 (d, 2H, J = 7.9 Hz), 3.96 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 146.8,
143.4, 136.9, 136.2, 133.2, 132.6, 131.8, 131.4, 129.7, 128.8, 128.2, 128.1, 127.8, 127.5, 126.8, 126.6,
126.3, 126.3, 117.8, 115.5, 31.7, 21.2; HRMS (ESI) m/z calculated for C25H20ClN2 [M+H]+ 383.1315,
found 383.1324 .
4-(6-Chloro-1-methyl-3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-diphenylaniline
(7h);
Compound was synthesized from 100 mg (0.311 mmol) of 6a; 90 mg, 60%; light yellow solid; mp:
175.4-177.6 °C ; 1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 7.59 (d, 1H, J = 7.3 Hz), 7.42 (t, 2H, J =
7.7 Hz), 7.36 (s, 1H), 7.34 (d, 2H, J = 8.5 Hz), 7.28 (t, 4H, J = 7.8 Hz), 7.16 (d, 4H, J = 7.7 Hz), 7.12
13
(d, 2H, J = 8.5 Hz), 7.04 (t, 2H, J = 7.3 Hz), 3.93 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ 147.7,
147.2, 146.6, 143.5, 134.4, 133.0, 131.4, 130.8, 129.3, 129.0, 128.7, 126.9, 126.8, 126.4, 124.7, 123.1,
122.7, 117.7, 115.4, 31.6; HRMS (ESI) m/z calculated for C32H25ClN3 [M+H]+ 486.1737, found
486.1751.
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6-Chloro-1-methyl-3-phenyl-5-(pyren-1-yl)-1H-pyrrolo[2,3-b]pyridine
(7i);
Compound
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synthesized from 6a; 150 mg, 68%, light brown solid; mp: 198.3-200.1 °C ; 1H NMR (500 MHz,
CDCl3) δ 8.32 (s, 1H), 8.24 (d, 1H, J = 7.8 Hz), 8.20 (d, 1H, J = 7.6 Hz), 8.15 (d, 1H, J = 7.5 Hz), 8.11
(s, 2H), 8.01-7.97 (m, 3H), 7.78 (d, 2H, J = 9.2 Hz), 7.59 (d, 2H, J = 7.4 Hz), 7.45 (s, 1H), 7.36 (t, 2H,
7.7 Hz), 7.22 (t, 1H, J = 7.4 Hz), 4.02 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 147.3, 144.8, 134.3,
134.2, 132.6, 131.4, 131.2, 130.9, 129.7, 129.0, 128.3, 127.9, 127.8, 127.6, 127.4, 127.0, 126.9, 126.5,
126.1, 125.4, 125.2, 125.1, 124.8, 124.5, 117.5, 115.5, 31.7; HRMS (ESI) m/z calculated for
C30H20ClN2 [M+H]+ 443.1315, found 443.1329
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6-Chloro-1-methyl-3-(naphthalen-2-yl)-5-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine
(7j);
1
Compound was synthesized from 6f; 125.6 mg, 67%; white solid ; mp: 113.9-115.5 °C; H NMR (500
MHz, CDCl3) δ 8.30 (s, 1H), 8.02 (s, 1H), 7.89 (d, 1H, J = 8.4 Hz), 7.86-7.83 (m, 2H), 7.71 (d, 1H, J =
13
8.2 Hz), 7.50-7.44 (m, 4H), 7.41-7.40 (m,1H), 7.36-7.35 (m, 1H), 3.95 (s, 3H); C{1H} NMR (126
MHz, CDCl3) δ 146.7, 143.5, 139.3, 133.9, 132.2, 131.8, 131.3, 129.4, 128.7, 127.8, 127.8, 127.4,
126.4, 125.6, 125.1, 124.8, 124.2, 124.1, 117.7, 115.4, 31.7; HRMS (ESI) m/z calculated for
C22H16ClN2S [M+H]+ 375.0722, found 375.0702 .
6-Chloro-1-methyl-5-(pyridin-4-yl)-3-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine
(7k);
Compound was synthesized from 6h; 107.6 mg, 66%; yellow solid; mp: 206.9-207.6 °C; 1H NMR (400
MHz, CDCl3) δ) δ 8.69 (d, 2H, J = 5.8 Hz), 8.08 ( s, 1H), 7.45-7.43 (m, 2H), 7.42 (dd,1H, J = 5.0 Hz,
3.0 Hz), 7.40 (s,1H), 7.38 (dd, 1H, J = 2.9 Hz, 1.3 Hz), 7.33 (dd, 1H, J = 4.9 Hz, 1.3 Hz), 3.93 (s, 3H);
13C{1H} NMR (101 MHz, ) δ 149.7, 147.1, 146.8, 142.6, 134.4, 131.2, 127.3, 126.5 126.4, 126.3,
124.9, 119.2, 117.8, 111.2, 31.7; HRMS (ESI) m/z calculated for C17H13ClN3S [M+H]+ 326.0518, found
326.0501 .
6-Chloro-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-phenyl-1H-pyrrolo[2,3-b]pyridine (7aʹ);
1
Compound was synthesized from 6aʹ; 186 mg, 82%; white solid; mp: 136.4-137.0 °C; H NMR (500
MHz, CDCl3) δ 8.14 (s, 1H), 7.55 (d, 2H, J = 7.4 Hz), 7.42 (d, 2H, J = 7.3 Hz), 7.37 (t, 2H, J = 7.0 Hz),
7.31 (s, 1H), 7.28-7.24 (m, 3H), 6.99 (d, 2H, J = 7.2 Hz), 6.87 (d, 2H, J = 7.4 Hz), 5.43 (s, 2H) 3.86 (s,
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3H), 3.78 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 159.4, 159.2, 146.4, 143.7, 134.4, 131.8, 131.5,
131.1, 129.4, 129.1,129.0, 128.9, 126.9, 126.4, 125.4, 117.7, 115.9, 114.3, 113.6, 55.35, 55.31, 47.7;
HRMS (ESI) m/z calculated for C28H24ClN2O2 [M+H]+ 455.1526 found 455.1523.
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General Procedure for synthesis of (8a-8j). In a sealed tube equipped with a magnetic stirrer
was added 7 (1 equiv., 0.3 mmol), Ar3-B(OH)2 (1.1 equiv.), Pd2dba3 (10 mol%), SPhos (20 mol%),
Cs2CO3 (2 equiv.) in Dioxane:Water (3:1, 5mL). The reaction mixture was stirred at 100 °C for 6-12 h
in an oil bath. The reaction was cooled down to room temperature and ethyl acetate was added to it. The
organic layer was washed with water followed by brine solution and dried with anhydrous sodium
sulphate. The organic layer was then evaporated using rotatory evaporator and purified through column
chromatography on silica gel (Ethyl acetate: Hexanes). The purified compounds (8a-8j) were obtained
in 42-79 % yields.
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5-(4-Methoxyphenyl)-1-methyl-3-phenyl-6-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (8a); Compound
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synthesized from 7a; 91 mg, 79%; white solid; mp: 167.5 -168.0 °C; H NMR (500 MHz, CDCl3) δ.
8.18 (d, 1H, J = 1.4 Hz), 7.66 (d, 2H, J = 8.0 Hz), 7.44-7.41(m, 3H), 7.35 (dd, 2H, J = 8.0 Hz, 1.7 Hz),
7.27 (t, 1H, J = 7.4 Hz), 7.15-7.14 (m, 2H), 7.06 (d, 2H, J = 7.7 Hz), 6.82 (d, 2H, J = 8.4 Hz), 3.97 (s,
3H), 3.80 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 158.3, 151.5, 147.7, 138.4, 136.9,
135.1, 134.3, 131.2, 130.4, 130.2, 129.0, 128.9, 128.5, 126.8, 126.0, 117.1, 114.8, 113.6, 55.3, 31.4,
21.3; HRMS (ESI) m/z calculated for C28H25N2O [M+H]+ 405.1967, found 405.1945.
5-(3,5-Bis(trifluoromethyl)phenyl)-1-methyl-3-phenyl-6-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine
(8b); Compound was synthesized from 7b; 65.8 mg, 43%; white solid; mp: 212.4 - 213.2 °C; 1H NMR
(500 MHz, CDCl3) δ 8.20 (s, 1H), 7.72 (s, 1H), 7.66-7.63 (m, 4H), 7.49-7.45 (m, 3H), 7.31 (t, 1H, J =
13
7.4 Hz), 7.22 (d, 2H, J = 8.0 Hz), 7.09 (d, 2H, J = 7.8 Hz), 4.00 (s, 3H), 2.33 (s, 3H); C{1H} NMR
(126 MHz, CDCl3) δ 151.8, 148.2, 144.0, 137.8, 137.1, 134.6, 131.3 (q, 2C, J = 33.1 Hz), 130.3 (d, 2C,
J = 2.7Hz), 130.1, 130.00, 129.1, 128.8, 127.5, 127.0, 126.4, 126.4, 123.3 (q, 2C, J = 272.8 Hz) 120.0-
119.9 (m, 1C), 117.4, 115.4, 31.4, 21.1; HRMS (ESI) m/z calculated for C29H21F6N2 [M+H]+ 511.1609,
found 511.1602.
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b]pyridine(8c); Compound synthesized from 7c; 107.6 mg, 68%; yellow solid; mp: 174.8-175.9 °C; 1H
NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.90 (s, 2H), 7.72 (s, 1H), 7.61-7.58 (m, 2H), 7.45 (s, 1H),
7.15-7.12 (m, 4H), 7.07 (d, 2H, J = 8.0 Hz), 4.01 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 161.6 (d, 1C, J = 245.5 Hz), 147.8, 147.7, 143.0, 137.4, 137.1, 130.8 (q, 2C, J = 33.1 Hz),
130.7, 130.5 (d, 2C, J = 3.0 Hz), 130.3, 130.0, 129.8, 129.3, 128.4 (d, 2C, J = 7.8 Hz), 127.9 , 123.4 (q,
2C, J = 272.6 Hz), 120.7-120.6 (m, 1C), 118.2, 115.9 (d, 2C, J = 21.4 Hz), 114.3, 31.4, 21.0; HRMS
(ESI) m/z calculated for C29H20F7N2 [M+H]+ 529.1514, found 529.1515.
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6-(Benzo[d][1,3]dioxol-5-yl)-5-(4-methoxyphenyl)-1-methyl-3-(p-tolyl)-1H-pyrrolo[2,3-
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b]pyridine (8d); Compound synthesized from 7d; 56.3 mg, 42%; white solid; mp: 127.1-127.7 °C; H
NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.54 (d, 2H, J = 7.7 Hz), 7.38 (s, 1H), 7.24 (d, 2H, J = 7.4 Hz),
7.15 (d, 2H, J = 8.3 Hz), 7.03 (s, 1H), 6.86 (d, 1H, J = 8.6 Hz), 6.83 (d, 2H, J = 8.4 Hz), 6.67 (d, 1H, J =
13
8.0 Hz), 5.93 (s, 2H), 3.96 (s, 3H), 3.81 (s, 3H), 2.38 (s, 3H); C{1H} NMR (126 MHz, CDCl3) δ
158.3, 150.8, 147.5, 147.2, 146.8, 135.7, 135.5, 134.2, 132.1, 131.1, 130.5, 129.6, 128.8, 126.8, 126.6,
124.5, 117.3, 114.9, 113.8, 110.8, 107.7, 100.9, 55.3, 31.3, 21.2; HRMS (ESI) m/z calculated for
C29H25N2O3 [M+H]+ 449.1865, found 449.1843.
3-(4-Methoxyphenyl)-1-methyl-6-(naphthalen-2-yl)-5-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (8e);
1
Compound synthesized from 7e; 90 mg, 66%; white solid; mp: 197.2-198.9 °C; H NMR (500 MHz,
CDCl3) δ 8.20 (s, 1H), 8.04 (s, 1H), 7.76 (s, 2H ), 7.66 (d, 1H, J = 8.4 Hz), 7.59 (d, 2H, J = 8.2 Hz),
7.50 (d, 1H, J = 8.3 Hz), 7.43-7.42 (m, 2H), 7.36 (s, 1H), 7.14 (d, 2H, J = 7.4 Hz), 7.03 (d, 2H, J = 7.6
13
Hz), 6.99 (d, 2H, J = 8.3 Hz), 4.00 (s, 3H), 3.84 (s, 3H), 2.31 (s, 3H); C{1H} NMR (126 MHz,
CDCl3) δ 158.2, 151.1, 147.8, 139.0, 138. 8, 136.1, 133.3, 132.6, 130.5, 130.1, 129.6, 129.5, 128.9,
128.5, 128.4, 128.0, 127.6, 127.5, 127.0, 126.5, 125.9, 125.7, 117.5, 114.7, 114.4, 55.4, 31.4, 21.1;
HRMS (ESI) m/z calculated for C32H27N2O [M+H]+ 455.2123, found 455.2120.
6-(3-Methoxyphenyl)-1-methyl-5-(naphthalen-2-yl)-3-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine (8f);
Compound synthesized from 7g; 94.2 mg, 69%; white solid; mp: 176.4-177.6 °C; 1H NMR (500 MHz,
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CDCl3) δ 8.31 (s, 1H), 7.85 (s, 1H), 7.80 (t, 2H, J = 6.1 Hz), 7.65 (d,1H, J = 8.4 Hz), 7.57 (d, 2H, J =
7.8 Hz), 7.48-7.45 (m, 2H),7.43 (s, 1H), 7.25 (d, 2H, J= 7.0 Hz), 7.21 (d, 1H,J=8.4 Hz), 7.10-7.07 (m,
2H), 7.01 (d, 1H, J = 7.5 Hz), 6.77-6.76 (m, 1H), 4.01 (s, 3H), 3.57 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3)δ 159.1, 151.1, 147.8, 142.4, 139.6, 135.9, 133.5, 132.0, 132.0, 130.9, 129.7, 129.2,
128.9, 128.8, 128.3, 127.9, 127.6, 127.2, 126.9, 126.8, 126.1, 125. 8, 123.2, 117.5, 115.6, 115.0, 113.6,
55.1, 31.4, 21.2; HRMS (ESI) m/z calculated for C32H27N2O [M+H]+ 455.2123, found 455.2124.
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1-Methyl-5-(naphthalen-2-yl)-3-phenyl-6-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine
(8g); Compound synthesized from 7f; 100.3 mg, 67%; white solid; mp: 197.0-198.0 °C; 1H NMR (500
MHz, CDCl3) δ 8.34 (s, 1H), 7.86 (s, 1H), 7.79 (m, 2H), 7.69-7.67 (m, 3H), 7.46-7.42 (m, 5H), 7.28 (t,
1H, J = 7.3 Hz), 7.23 (d, 1H, J = 7.4 Hz), 6.73 (s, 2H), 4.03 (s, 3H), 3.80 (s, 3H), 3.49 (s,6H); 13C{1H}
NMR (126 MHz, CDCl3)δ 152.6, 151.0, 147.8, 139.7, 137.5, 136.2, 134.9, 133.5, 132.0, 130.9,
129.4,129.0, 128.8, 128.2, 128.8, 127.8, 127.6, 127.4, 127.2, 126.9, 126.2, 125.9, 117.4, 115.1, 107.9,
60.9, 55.8, 31.5; HRMS (ESI) m/z calculated for C33H29N2O3 [M+H]+ 501.2178, found 501.2151.
6-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-5-(naphthalen-2-yl)-3-phenyl-1H-pyrrolo[2,3-b]
pyridine (8h), Compound was synthesized from 7f; 75.2 mg, 55%; white solid; mp: 186.8 -187.5 °C; 1H
NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.86 (s, 1H), 7.81-7.80 (m, 2H), 7.67-7.66 (m, 3H), 7.49-7.41
(m, 5H), 7.27 (t, 1H, J = 7.3 Hz), 7.23 (d, 1H, J = 9.8 Hz), 7.12 (s, 1H), 6.86 (d, 1H, J = 8.0 Hz), 6.59
(d, 1H, J = 8.1 Hz), 5.90 (s, 2H), 4.00 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 151.0, 147.8, 147.3,
147.0, 139.7, 135.3, 135.0, 133.6, 132.1, 131.0, 129.2, 129.0, 128.9, 128.2, 127.9, 127.7, 127.3, 127.0,
126.9, 126.13, 126.07, 125. 8, 124.7, 117.3, 115.1, 110.8, 107.7, 100.9, 31.4; HRMS (ESI) m/z
calculated for C31H23N2O2 [M+H]+ 455.1759, found 455.175.
1-Methyl-6-(pyridin-3-yl)-5-(pyridin-4-yl)-3-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine
(8i);
Compound was synthesized from 7i; 46.2 mg, 42%; yellow solid; mp: decompose; 1H NMR (500 MHz,
DMSO-d6) δ 8.53-8.50 (m, 4H), 8.43 (s, 1H), 8.11 (s, 1H), 7.94-7.93 (m, 1H), 7.75-7.74 (m, 1H), 7.65
(dd, 1H, J = 4.9 Hz, 2.8 Hz), 7.60 (dd, 1H, J = 4.9 Hz, 1.0 Hz), 7.36 (dd, 1H, J = 7.7 Hz, 4.9 Hz), 7.31
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