Cu(II)-catalyzed sulfonylation of 7-azaindoles using DABSO as SO2-Source and its mechanistic study

Article abstract of DOI:10.1016/j.tet.2020.131337

DABSO mediated sulfonylation of iodinated 7-azaindoles was achieved for the first time through sulfonylative Suzuki-Miyaura cross coupling (SMC) reaction under mild conditions giving good yields of sulfonylated 7-azaindole derivatives. Interestingly, control experiments suggest that present method involves in-situ generation of ArSO₂ free radical followed by the key steps of SMC reaction. Scope of the reaction was explored with both electronically different and bulky group carrying boronic acids as coupling partner. The sulfonylation is scalable and occurred selectively at iodo group, irrespective of its position on azaindole. Moreover, the proposed mechanism has been supported by electron paramagnetic resonance (EPR) and density functional theory (DFT) calculations.

Full text of DOI:10.1016/j.tet.2020.131337

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Cu(II)-catalyzed sulfonylation of 7-azaindoles using DABSO as SO -Source and its
2
mechanistic study
Urvashi, Mohammad Ovais Dar, Prasad V. Bharatam, Parthasarathi Das, Shrikant
Kukreti, Vibha Tandon
PII:
S0040-4020(20)30492-0
https://doi.org/10.1016/j.tet.2020.131337
TET 131337
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 April 2020
Revised Date: 20 May 2020
Accepted Date: 8 June 2020
Please cite this article as: Urvashi , Dar MO, Bharatam PV, Das P, Kukreti S, Tandon V, Cu(II)-catalyzed
sulfonylation of 7-azaindoles using DABSO as SO -Source and its mechanistic study, Tetrahedron
2
(2020), doi: https://doi.org/10.1016/j.tet.2020.131337.
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Cu(II)-Catalyzed Sulfonylation of 7-
Azaindoles using DABSO as SO2-Source and
its Mechanistic Study
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Urvashia,d, Mohammad Ovais Darb, Prasad V. Bharatamb, ParthasarathiDasc,*, Shrikant Kukretia, and Vibha
Tandond, *
aDepartment of Chemistry, University of Delhi, Delhi-11000, India
bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
Sector-67, S.A.S. Nagar – 160062 Punjab, India
cDepartment of Chemistry, Indian Institute of Technology (ISM), Dhanbad, Jharkhand-826004, India
d Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067, India

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Cu(II)-Catalyzed Sulfonylation of 7-
Azaindoles using DABSO as SO2-Source and
its Mechanistic Study
Leave this area blank for abstract info.
Urvashia,d, Mohammad Ovais Darb, Prasad V. Bharatamb, Parthasarathi Dasc,*, Shrikant Kukretia, and Vibha
Tandond, *
aDepartment of Chemistry, University of Delhi, Delhi-11000, India
bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
Sector-67, S.A.S. Nagar – 160062 Punjab, India
cDepartment of Chemistry, Indian Institute of Technology (ISM), Dhanbad, Jharkhand-826004, India
d Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067, India

1
Tetrahedron
journal homepage: www.elsevier.com
Cu(II)-Catalyzed Sulfonylation of 7-Azaindoles using DABSO as SO2-Source and its
Mechanistic Study
Urvashia,d, Mohammad Ovais Darb, Prasad V. Bharatamb, Parthasarathi Dasc,*, Shrikant Kukretia, and
Vibha Tandond, *,
aDepartment of Chemistry, University of Delhi, Delhi-11000, India
bDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar – 160062 Punjab, India
cDepartment of Chemistry, Indian Institute of Technology (ISM), Dhanbad, Jharkhand-826004, India
d Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi-110067, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
DABSO mediated sulfonylation of iodinated 7-azaindoles was achieved for the first
time through sulfonylative Suzuki-Miyaura cross coupling (SMC) reaction under mild
conditions giving good yields of sulfonylated 7-azaindole derivatives. Interestingly, control
experiments suggest that present method involves in-situ generation of ArSO2 free radical
followed by the key steps of SMC reaction. Scope of the reaction was explored with both
electronically different and bulky group carrying boronic acids as coupling partner. The
sulfonylation is scalable and occurred selectively at iodo group, irrespective of its position
on azaindole. Moreover, the proposed mechanism has been supported by electron
paramagnetic resonance (EPR) and density functional theory (DFT) calculations.
Available online
Keywords:
Keyword_1
Keyword_2
Keyword_3
Keyword_4
Keyword_5
2009 Elsevier Ltd. All rights reserved
.
A) Biological relevance of 7-azaindole
H
1. Introduction
CF3
F
N
N
Cl
N
O
Cl
O
S
7-Azaindole, a bioisosteric replacement of indole is found to
be a prominent and pivotal target for the synthetic community,
realizing its potency in plethora of medically beneficial
activities.1 Two drugs named Vemurafenib and Venetoclax,
containing a 7-azaindole core are approved by FDA and several
other 7-azaindole-containing species are in various stages of
O
N
F
N
Pexidartinib
CSF1R, Phase 3
N
H
H
N
N
H
Vemurafenib
Cl
Me
HN
BRAF inhibitor
HN
N
N
N
O
O
O
N
H
N
N
O
2
S
O
O
N
O
clinical development (Fig.1A). One report on 1-aminoethyl-3-
H
N
arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as potent 5-HT6 agonists
shows the importance of sulfonyl azaindole compounds.2g Due
to their medicinal/material properties, methods for the synthesis
and functionalization of azaindole and its derivatives have
attracted considerable interest.3 The development of transition-
metal-catalyzed reactions for the functionalization of
heterocycles continues to be an active area of research.4 In
particular, C-sulfonylation is a favored organic transformation for
the prospective enhanced biological features in heteroarenes.5
S
O
O
Venetoclax
BCL-2 inhibitor
F
5-HT6 agonist
18
O2
S
B)
Previous work: Willis et al.
(HO) B
O
S
R2
Cu(I)
DABSO
O
I +
2
R2
R1
R1
sulfinate intermediate
R2
This work
B(OH)2
I
O2S
Cu(II)
R1
+
R1
t
t
Bu
Bu
N
N
N
N
R2
N
In recent years, DABSO has become a reagent of choice for
the sulfonylation reactions as compared to other SO2-surrogates
due to its bench stability, commercial availability and easy
handling.6 Initially, Willis et al.7a-b and Rocke et al.8
recommended DABSO for the in-situ formation of sulfinates
PMB
1
2
PMB
N
N L4
4a 4zf
(28-78%)
-
N
SO2
SO2
Free radical Pathway
4q
DABSO (3) as SO2 Surrogate
Fig. 1. [A] Biological relevance of azaindole [B] sulfonylative
Suzuki-Miyaura cross coupling.

2
Tetrahedron
Scheme 1. Preparation of iodo-substituted 7-azaindoles (1a-1i). Reaction conditions: (i) under Ar atm., alkyne (1.2 equiv.), CuI (5 mol
%), PdCl2(PPh3)2 (5 mol %), NEt3 (1.3 equiv.), DMF, 120 °C, 6-8 h; (ii) Ar-B(OH)2 (1.2 equiv.), Pd(OAc)2 (5 mol %), dppf (5 mol %),
Cs2CO3 (2 equiv), 1,4-dioxane, 90° C, 1 h; (iii) NIS (1 equiv.), KOH (0.5 equiv.), DCM, 1 h, r.t.; (iv) iodoanisole (1.1 equiv), AgOTf
(1.2 equiv.), dry DMF, Pd(OAc)2 (10 mol%), o-nitrobenzoic acid (1.5 equiv.), 120° C, 3 h.
to fabricate sulfonamides afterwards sulfone synthetic protocols
from organolithium/ magnesium9 and organozinc reagent10 were
outlined. Synthesis of diverse range of important frameworks can
be accomplished via sulfonylative alkyne chemistry,11 reductive
Table 1. Optimization reactions for the synthesis of 4j by
coupling of 1a and boronic acid 2a.
fluoroalkyl
sulfination,12
regio-
and
stereospecific
selenosulfonation,13 C(sp2)–H arylsulfonylation14 and oxidant or
metal free strategy15 concomitant with DABSO.16 Notably,
palladium and copper catalyzed direct C-H functionalization of
indoles17a and imidazopyridines17b through SO2 fixation was
disclosed by certain groups. There are already reports on Cu(I)-
catalyzed sulfonylative Suzuki–Miyaura cross-coupling between
boronic acids, DABSO, and aryl iodides18 (Fig.1B). Although
coupling on substrate such as indole, pyrrole and quinolones is in
the list, but they have not show it on pyridine fused rings, but
overall yield of sulfonylated product on pyridine was 39% only.
Based on the considerations above, this is first report of DABSO
mediated sulfonylative SMC on hetrocyclic azaindole through
free radicals. In continuation of our earlier work on Suzuki-
Miyaura coupling studies on heteroaromatics,19 a convenient
copper (II) activated sulfonylative Suzuki-Miyaura coupling of
azaindoles employing DABSO is being reported in this
manuscript (Fig. 1B). The EPR and DFT calculations suggest
that reaction is going through a free radical pathway.
4j´
4j
Entry
Cu-catalyst
L
Solvent
(%) (%)
1
2c
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4PF6
Cu2O
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
ACN
DMPU
DMF
DMF
DMF
DMF
18
15
45
25
38
41
n.r.
58
36
32
21
25
21
--
49
58
31
39
34
55
n.r.
40
24
68
78
60
71
78
58
66
n.r.
56
42
n.r.
3
4d
5e
CuBr
6
7
Cu(acac)2
Cu(OTf)2
Cu(NO3)2.3H2O
Cu(acac)2
CuF2
8
9f
10
11
12
13
14
15
16
17g
18h
19i
20
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
2. Results and discussion
--
22
n.r
--
45
n.r.
Preparation of Iodo-7-azindoles: A variety of iodo-7-
azaindole (1a-1i) were synthesized from commercially available
7-azaindole to access the product. Literature method of
iodination,3d, 19a N-oxidation,19b chlorination19a and N-protection19a
were employed to gain iodo-7-azaindole as starting material in
good to excellent yields. C-5 Br group was utilized to prepare 1e
and 1f readily through Suzuki-Miyaura and Sonogashira cross-
coupling reactions, while 1h is synthesized by Finkelstein
reaction20f for exchange of Cl-I group. Compound 1i is prepared
from C-H activation procedure given by Larossa et al.20a
CuF2
--
Reaction conditions: 1a (80 mg, 0.2 mmol, 1.0 equiv.), DABSO
(72 mg, 0.3 mmol, 1.5 equiv.), 2a (29 mg, 0.24 mmol, 1.2
equiv.), CuF2 (20 mol %), L4 (20 mol %), dry DMF (0.067 M, 3-
The investigations began by establishing suitable reaction
conditions for the coupling between 6-chloro-3-iodo-1-(4-
methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine (1a) and phenyl
boronic acid (2a) in the presence of DABSO (3) (Table 1)
leading to desired product 4j. The dihalogenated azaindole was
chosen in order to monitor selectivity of reaction.
b
c
d
5 mL), N2 atm., Isolated Yields, PG = Me, 15 % starting
recovered, e12% starting recovered, 25% starting recovered,
f
greaction at rt, reaction at 80°C and 35 % starting recovered,
h
ireaction at 130° C, n. r. = No reaction.

3
Initially we have pursued Willis strategy of Cu(MeCN)4BF4
catalyst with bipyridyl ligand (L1) in DMF at 100°C, which gave
4j in 49% of yield with 18% of non-sulfonylated C-C coupling
product 4j´(Table 1, entry 1). We have used N-methyl protected
azaindole but no improvement in the yield of 4j was observed.
When we changed the counter anion (PF6)- 31% of sulfonylated
product was obtained. However, inferior results were obtained
with other copper salts e.g. Cu2O, CuBr, Cu(acac)2 (entries 4-6),
while Cu(OTf)2 failed to produce any desired product. (entry 7).
Pleasingly, an increased yield of 68% was obtained with CuF2
(entry 10). Use of nitrogen atmosphere promoted the yield to
78% but deterrent non-sulfonylative coupling product 4j´
remains a big hurdle (Table 1, entry 11). This reaction was also
explored in other bipyridyl ligands, but almost similar results
were obtained. Addition of 4,4′-di-tert-butyl-2,2′-dipyridyl as
ligand in dried DMF and nitrogen atmosphere at 100°C, gave
78% 4j exclusively (Table 1entry 14). Compound 4j was
isolated in low yield on solvent variation (Table 1, entries 17-18).
Further, appropriate temperature was investigated as one of the
requirement of sulfonylation reaction (Table 1, entry 17-19).
Table 1, entry 20 suggests that catalyst is necessary for reaction.
Therefore, optimized reaction conditions are as follows: 1a
(1equiv.), 2a (1.2 equiv.), DABSO (1.5 equiv.), CuF2 (20 mol
%), L4 (20 mol %), in dry DMF under nitrogen atmosphere at
100 °C (Table 1, entry 14).
To determine the viability of proposed method, sulfonylative
coupling at C-3 position of 3-iodo 7-azaindoles (Table 2) was
investigated first. Boronic acids having electron donating (EDG)
and electron withdrawing groups (EWG) efficiently coupled with
the unsubstituted C3-iodo 7-azaindoles to give 4a-4c in 45-60%
Table 2. Scope of the sulfonylative Suzuki-Miyaura coupling for the substituted Iodo 7-azaindolea,b
(1a-d,
1g)
(1a-d,
1g)
Entry
(2a-w)
4a-z ( Yield)a,b
Entry
(2a-w)
4a-z ( Yield)a,b
1b
1b
1
7
1c
2b
4a, 54%
4g, 28%
2h
2
3
8
9
1c
4b, 60%
4h, 68%
2c
2i
1b
1c
1a
4c, 45%
4i, 71%
4j, 78%
2d
2j
4
5
10
11
12
1b
1b
4d, 64%
2e
2f
2a
2k
O2S
1a
1a
N
N
PMB
4e, 35%
4k, 57%
4l, 52%
6
1c
4f, 54%c
2g
2l

4
Tetrahedron
13
14
15
16
21
1a
1a
1g
1d
1d
1d
1d
4m, 46%
4u, 59%
2m
2o
22
23
24
4n, 42%
4o, 35%
4v, 64%
4w, 53%
2n
2s
2t
2o
2a
1d
1d
4p, 45%
4q, 67%
4x, 59%
4y, 54%
2u
2v
17
18
25
26
27
1d
2l
1d
1d
1h
4r, 54%
4z, 49%
2p
2w
19
20
1d
1d
2c
4s, 51%
4t, 57%
4zd, 50%
2q
2r
aReaction conditions: 1a (0.5 mmol, 1.0 equiv.), DABSO (0.75 mmol, 1.5 equiv), 2a (0.6 mmol, 1.2 equiv.), CuF2. (20 mol %),
L4 (20 mol %), dry DMF (3-5 mL), N2-atm, 6-12 h, 100 °C, bIsolated yield. c15-18 h.
yield. The flat aromatic system 4d & 4e could be obtained in
64% and 35% yield respectively. Interestingly, C-5 Br-
substituted 3-iodo-7-azaindoles too showed constructive
sulfonylation where 4-pyridyl boronic acid smoothly proceeded
to yield 54% of 4f. Treatment of bulky 2-naphthyl and
anthracene-2-boronic acid provided the desired products in good
range of yield (68-71%, 4h-4i). Compound 3-thienyl sulfonylated
7-azaindole 4g was synthesized in 28% yield only. The
sulfonylation of 6-chloro-7-azaindoles were explored to examine
the effect of electronic variability on sulfonylation reaction.
Vinyl boronic acid was also investigated as coupling partner
to synthesize 4n in 42% yield. Similarly, C-4 chloro substituted
3-iodo-7-azaindole also afforded C-3 sulfonylated product 4o as
a demonstration of synthetic elaboration of reaction
Further, sulfonylative coupling to C6-methoxylated-3-iodo
azaindole was performed using electronically different aryl
boronic acids in the three component reaction to get 4p-4z in
moderate to good yield. The reaction showed good tolerance
towards functional groups such as -NO2, -SMe, -CN, -OH, -CHO
to get 4r, 4t-4u, 4w-4x in good yield. Further, bicyclic
heteroaryls containing boronic acids were reacted with 6-
methoxy substituted 7-azaindoles to get 4y (49 % yield) and 4z
(54% yield). Importantly, 4-iodo-7-azaindole prepared by
Finkelstein reaction, furnished 4zd in 50% yield.
Remarkably,
good
yield
of
1-(4-methoxybenzyl)-3-
(phenylsulfonyl)-1H-pyrrolo[2,3-b] pyridine (78%, 4j) was
achieved. Installation of 3-Me, 4-F and 4-OCF3 substituted
phenyl boronic acid was carried out in 46–57% of yield (4k-4m)
in the case of 6-chloro-7-azaindole.

5
This methodology is also useful in conjunction with C-C
cross-coupling reactions such as Suzuki-Miyaura (4za-4zc) or
Sonogashira coupling (4ze) for example; coupling of sterically
hindered 2-methylphenyl boronic acid results 35% of 4zb. C-2
arylated 7-azaindoles synthesized by C-H activation20a was also
studied as substrate with trans-2- phenylvinyl boronic acid and
4zf was isolated in moderate yield of 40% (Scheme 2).
analysis, which is given in supplementary information (Fig. S1
to S4).
To gain insights into the mechanism of the reaction, control
experiments were performed (Scheme 3). Under standard
conditions, the reaction was inhibited with TEMPO (eq 1). This
observation suggests that the reaction is proceeding through a
radical pathway which is different from the earlier report.18. The
present methodology failed to produce the desired 4j when
readily prepared sulfinate was used as sulfonylation source (eq
2). The reaction did not work either in absence of DABSO or in
presence of DABCO (eq 1 and 3), suggesting a different
mechanism of sulfonylation as compared to sulfinate mediated
sulfonylation.18 The reaction underwent in dark (eq 3), which
eliminates the possibility of light mediated homolysis of iodine.21
This reaction is selective to iodo group on heterocyclic ring,
irrespective of its position. Reaction did not go on chloro or
bromo substituents. EPR proved the formation of delocalized free
radical (g = 2.004) after 10 mins, except for paramagnetic Cu (II)
(g = 1.992) (Scheme 3 (4)). Formation of Cu(I) in the reaction
medium is evidenced by a decreased intensity of Cu(II) in time
dependent EPR experiment [Scheme 3(5)].
The gram scale reaction using the standard conditions
yielded 70% of the desired product 4j (Scheme 4). The
deprotection of p-methoxybenzyl group (PMB) is carried out on
4j to yield free NH- group, using trifluoroacetic acid (TFA)
(Scheme 5).22
Scheme 2. Sulfonylative Suzuki-Miyaura coupling, reaction
conditions: 1a (0.5 mmol, 1.0 equiv.), DABSO (0.75 mmol, 1.5
equiv.), 2a (0.6 mmol, 1.2 equiv.), CuF2 (20 mol %), L4 (20 mol
%), dry DMF (3-5 mL), N2-atm, 6-12 h, 100 °C, Isolated yield.
Scheme 4. Large Scale Synthesis of 4j
Scheme 5. Deprotection of PMB.
To explore the energy profile of the catalytic step of the
reaction, quantum chemical calculations were performed using
density function B3LYP method. The 3D structures of all the
species and their absolute energy values are provided in
supplementary information. The overall energy of the reaction
requires about 27 kcal/mol (endergonic). However, the
participation of the catalyst is facilitating the reaction (Fig. 2), by
releasing ~36.1 kcal/mol energy. The energy profile of the
reaction indicates the formation of an intermediate complex C,
which is ~24 kcal/mol less stable than the starting species 1a’ and
B.
4)
5)
Based on the aforementioned experimental observations and
previous reports, a plausible mechanism was proposed (Scheme
6). Initially, Cu(II) gets reduced to Cu(I) in the presence of L4
ligand to generate A.23 Meanwhile, arylsulfonyl radical is
produced by reaction of boronic acid and DABSO.24 Afterwards,
arylsulfonyl radical combines with the species A , forming Cu(I)-
S bond (B) followed by oxidative addition of 1a, which affords
the intermediate (D). Finally, the intermediate (D) undergoes
Scheme 3. Control Experiments. [4] EPR spectra of A) Reaction
mixture (1a + 2a + 3 + CuF2+ L4) in DMF at 100°C at 10 mins,
B) at 0 mins C) CuF2+ L4 in DMF at 0 mins. [5] Reaction
mixture (1a + 2a + 3 + CuF2+ L4) in DMF at 100°C at different
time points.
The structure of two compounds 4q and 4x was
unambiguously confirmed through X-ray crystal structure

6
Tetrahedron
reductive elimination, leading to the desired product 4j, and
Unless otherwise noted, all reagents were
release CuI, followed by halogen exchange generate Cu(I)F.
purchased from commercial suppliers and used without
purification. All Sulfonylative 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 nm UV light and
Iodine, ninhydrin stains. Melting points were recorded on
Büchi Melting Point B-545 instrument and are uncorrected.
1H NMR and 13C NMR spectra were recorded with a 400
MHz (1H = 400 and 13C = 100 MHz) or 500 MHz (1H = 500
and 13C = 125 MHz) spectrometer. Chemical shifts value of
1H NMR were recorded in parts per million (ppm, δ) relative
to tetramethylsilane (TMS, 0.00 ppm). Multiplicities are
indicated as 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 13C
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). High-
resolution mass spectra (HRMS) were obtained using ESI-
TOF method. EPR: Electron Paramagnetic Resonance
spectra were recorded using Bruker EMX 1444 EPR
spectrometer
operating
at
9.66
GHz.
Diphenylpicrylhydrazyl, DPPH (g = 2.0037), was used for
the calibration of EPR spectrometer. Infrared measurements
were carried out as liquid films on NaCl discs or as a KBr
disc using a Perkin-Elmer 1600 series FTIR spectrometer
and Bruker Tensor 27 FT-IR with internal calibration in the
range 4000- 500 cm-1. MALDI-TOF MS measurements were
performed with AB SCIEX TOF/TOF 5800 System with
ekspert nanoLC 400 and EKSpot MALDI Spotter without
using any matrix.
Fig. 2. Energy Profile diagram of the sulfonylation step using
B3LYP3 function with the 6-31+G(d) basis set for H, C, N, S and
O atoms, and LAN2LDZ4 basis set for Cu and I. The two
transition states are shown as TS1 and TS2.
Cu(II)F2
t-Bu
t-Bu
4.1.2. Reagents.
ArB(OH)2 + DABSO
Cu(I)
L =
All reagents were used directly as obtained
commercially unless otherwise noted. Anhydrous forms of
dimethylformamide, acetonitrile, dimethyl sulfoxide,
diethylether, THF, hexanes, ethyl acetate, and CH2Cl2 were
purchased from Merck Chemical Co. 7-Azaindole, 5-bromo-
N
N
L
ArSO2• + DABCO+•
Cu(I)F
A
Inter
halogen
exchange
-F
L
Cu(I)
SO2Ar
B
CuI
7-Azaindole,
p-methoxybenzylchloride, silver triflate,4-
I
L
iodoanisole, PdCl2(PPh3)2, dppf, terminal alkynes,
palladium(II) acetate, Et3N and the copper salts were
purchased from Aldrich Chemical Co. Inc.
O2S
N
SO2Ar
I
Cu
(III)
N
PMB
Cl
N
N
PMB
Cl
N
Cl
N
4.1.3. Preparation of starting Iodo-7-azindoles
PMB
D
4j
1a
A
variety of iodo-7-azaindole
synthesized by commercially available 7-azaindole to access
the designed strategy. The 1a was prepared from 1
pyrrolo[2,3- ]pyridine with general procedure A, B, C and
D, 1b was synthesized from 1 -pyrrolo[2,3- ]pyridine with
general procedure C and D, 1c was synthesized starting from
5-bromo-1 -pyrrolo[2,3- ]pyridine with general procedure
C and D, 1d was syntheiszed from 1 -pyrrolo[2,3-
]pyridine with general procedure A, I, C, D, 1g was
synthesized from 4-chloro-1 -pyrrolo[2,3- ]pyridine with
(
1a-1i
)
were
Scheme 6. Plausible mechanism
H-
3. Conclusions
b
H
b
In conclusion, successful incorporation of SO2 to
construct a C-S-C bond via copper catalyzed Suzuki-Miyaura
sulfonylative coupling reaction has been attained. Here, in situ
free radical formation followed by Suzuki-Miyaura coupling
steps are the route to sulfones using DABSO as an SO2 surrogate.
Interestingly, no free radical initiators were used for this reaction.
The proposed mechanism is supported by DFT calculation.
Overall, we have developed an efficient method to synthesize
medicinally important azaindolyl sulfones in good yields.
H
b
H
b
H
b
general procedure C and D. C-5 Br group was utilized to
prepare 1e and 1f readily through cross-coupling reactions
on 5-bromo-1
pyrrolo[2,3- ]pyridine respectively. The 1h was synthesized
from 4-chloro-1 -pyrrolo[2,3- ]pyridine with general
procedure H and D. Compound 1i is synthesized from 1
pyrrolo[2,3- ]pyridine with general procedure D, G and C.
H-pyrrolo[2,3-b]pyridine and 5-bromo-1H-
b
4. Experimental
H
b
H-
4.1.1. General Information
b
All general methods are written below for the ease of
undersanding. The structure and purity of starting materials

7
and intermediates were confirmed by their physical and
spectral data.
General method (A) for Iodination3d,19a-b
TLC), the reaction was allowed to cool to room temperature.
The reaction mixture was extracted with ethyl acetate and organic
layer was washed with brine. The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure. The
resulting residue was purified by column chromatography (silica
gel, hexane/EtOAc) to give the desired product. This method has
been followed up for getting 1e.
In a mixture of
1H-pyrrolo[2,3-b]pyridine (1 g, 1
equiv, 8.4 mmol) in CH2Cl2 was added KOH (235 mg, 4.2
mmol, 0.50 equiv.) at rt. After 30 min, N-iodosuccinimide (1.88
g, 8.4 mmol, 1.00 equiv) was added, and the mixture was stirred
for 10 h, quenched with a saturated solution of Na2S2O3, and
extracted with CH2Cl2. The combined organic layers were dried
and evaporated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/EtOAc, 98:2) to
give pure iodinated product. This method has been followed up
for getting iodinated starting material (1a-1i).
General method (F) for Sonogashira reaction19a
A
solution of 5-bromo-1-(4-methoxybenzyl)-1H-
pyrrolo[2,3-b]pyridine 5a (100 mg, 0.315 mmol), alkyne (38.7
mg, 1.2 equiv., 0.37 mmol), PdCl2(PPh3)2 (11.1 mg, 0.05 equiv.,
0.01 mmol), CuI (3.0 mg, 0.05 equiv., 0.01 mmol), NEt3 (41.6
mg, 1.3 equiv., 0.41 mmol) in DMF (3 mL) was heated to 120 oC
under N2-atmosphere till reaction completed as indicated by
TLC. The reaction was allowed to come to rt. The reaction
mixture was extracted with ethyl acetate and organic layer was
washed with brine. The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by column chromatography (silica gel,
hexane/EtOAc) to give the desired product. This method has
been followed up for getting 1f .
9a-b
General method (B) for N-oxide formation 1
:
To a solution of 1
H
-pyrrolo[2,3-
b]pyridine (1 g, 1
equiv, 8.4 mmol) in diethyl ether (50 mL) was added 77%
m-chloroperbenzoic acid (21.1 mmol, 3.65 g, 2.5 equiv)
portion wise. Then reaction mixture was stirred at rt for 1 h
until a precipitation occurs. After the completion of reaction
as monitored by TLC, it was filtered and dried. The obtained
white solid added to 200 mL of distilled water, and saturated
solution of potassium carbonate was slowly added to it, until
pH of soultion reaches to 9−10. The mixture was stirred
overnight, filtered, and dried to get an off-white solid. This
method has been used in the preparation of 1a and 1d as
written in above sequence.
General method (G) for C-H activation20a
To the mixture of 1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridine 5b (100 mg, 0.41 mmol, 1.00 equiv.), iodoanisole
(108 mg, 0.46 mmol, 1.1 equiv), AgOTf (129 mg, 0.5 mmol, 1.2
equiv.), dry DMF (10ml), added Pd(OAc)2 (9.4 mg, 0.041 mmol,
10 mol%) and o-nitrobenzoic acid (105 mg, 0.62 mmol, 1.5
equiv.). The reaction mixture is allowed to stirred at 120° C for 3
h under N2-atm. till completion of reaction as monitored by TLC.
The reaction was allowed to cool to rt. The reaction mixture was
extracted with ethyl acetate and organic layer was washed with
brine. The combined organic layers were dried over anhyd.
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by column chromatography (silica gel,
hexane/EtOAc) to give the desired product. This method is used
for synthesis of 1i .
9a-b
General method (C) for Chlorination1
:
To a solution of 3-iodo-1
H-pyrrolo[2,3-b]pyridine
7-oxide (1g, 3.8 mmol, 1 equiv) in dry THF, the N2 was
purged and an inert atmosphere was maintained. Added
HMDS (620 mg, 3.8 mmol, 1 equiv), followed by slow
addition of trichloroacetyl chloride (1.74 g, 9.6 mmol, 2.5
equiv) with constant stirring (ice bath). Then reaction
mixture was stirred at room temperature for 1h and
monitored using TLC. After completion, evaporated the
THF and the mixture was extracted using EtOAc and
washed with saturated solution of sodium bicarbonate. The
organic layer was dried using anhydrous sodium sulfate and
evaporated. Purification was done by using column
chromatography on silica gel using ethyl acetate/hexane
(30:70) to obtain a white solid. This method has been
utilized for the preparation of 1a.
General method (H) for Finkelstein reaction20f
To solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (1 g,
7.4 mmol), NaI (1.34 g, 1.2 equiv., 8.9 mmol), in MeCN (15 mL
), AcCl (0.567 g, 1.1 equiv., 7.2 mmol) was refluxed under N2
atm. till reaction completed as indicated by TLC (1.5h) stained
with Iodine. The reaction was allowed to cool to room
temperature. The reaction mixture was neutralized with 2M
NaOH solution and solvent was evaporated, then it was taken in
THF (10 ml) and stirred for next 12h at 40°C temperature. THF
was evaporated and it was extracted with ethyl acetate and
organic layer was washed with brine. The combined organic
layers were dried over anhyd. Na2SO4 and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography (silica gel, hexane/EtOAc) to give the desired
product. This method is followed up for the synthesis of 1h.
General method (D) for N-protection3a,19a-b
To a solution of 3-iodo-1H-pyrrolo[2,3-b]pyridine (2
g, 8.2 mmol) in dry DMF (5 mL), added slowly K2CO3 (3.39 g, 3
equiv., 24.6 mmol) and stirred for 10 min. 4-Methoxybenzyl
chloride (1.66 g, 1.3 equiv., 10.6 mmol) was added to solution
and stirred the reaction mixture at rt. After the completion of
reaction as indicated by TLC, the reaction was quenched with a
sat. aq. NH4Cl solution. The crude reaction mixture was extracted
three times with CH2Cl2 and dried over anhyd. Na2SO4. After
filtration, the solvent was removed in vacuo. Purification was
General method (I) for methoxylation reaction20f
done by column chromatography to furnish solid/oil
. This
Under argon the 1H-pyrrolo[2,3-b]pyridine 7-oxide
method has been followed for getting 1a-1i as mentioned above.
(3.0g, 22.39 mmol) was dissolved in dry MeCN (75 ml).
Dimethylsulfate (2.37 ml, 24.62 mmol), was added and the
reaction mixture was stirred at 65° C for 12 h. A CH3ONa
solution (3.08 g of sodium in 26 g of methanol) was added
dropwise and the mixture was stirred for extra 20 h at 60° C.
Then the reaction mixture was quenched with the acetic acid
untill pH 7 was reached and concentrated. After dissolution
it into DCM, the organic layer was washed with 1M sodium
bicarbonate solution. The aqueous layer was combined and
General method (E) for Suzuki-Miyaura reaction19a
A solution of 5-bromo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridine 5a (100 mg, 0.315 mmol), boronic acid (42.4 mg, 1.1
equiv., 0.34 mmol), Pd(OAc)2 (3.5 mg, 0.05 equiv., 0.01 mmol),
dppf (8.7 mg, 0.05 equiv., 0.01 mmol), Cs2CO3 (206.1 mg, 2
equiv., 0.63 mmol) in 1,4-dioxane : water (3:1, 3 mL) was heated
to 90oC for 1 h. After the reaction was completed (monitored by

8
Tetrahedron
extacted with ethyl acetate and dried over Na2SO4. The
Yield = 236.8 mg (74%); pale yellow color solid; mp =
155-156 °C; 1H NMR (500 MHz, CDCl3) δ (ppm): 8.57 (d,
= 2.0 Hz, 1H), 7.84 (d, = 2.1 Hz, 1H), 7.61-7.59 (m, 2H),
7.29 (s, 1H), 7.24 (d, = 8.6 Hz, 2H), 7.06-7.04 (m, 2H),
solvent was removed in vacuo and purification was done by silica
gel column chromatography (hexane/EtOAc, 9:1) to furnished
white solid. This method has been worked for synthesis of 1d
J
J
.
J
6.89-6.87 (m, 2H), 5.45 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H).
13C{H} NMR (125 MHz, CDCl3) δ (ppm): 159.3, 159.1,
146.5, 143.3, 132.2, 131.6, 130.3, 129.2, 129.1, 128.5,
127.1, 123.0, 114.4, 114.2, 55.4, 55.3, 53.9, 47.7. HRMS
calcd. for C22H20IN2O2 (M+H+): 471.0569. found: 471.0573.
4.1.4. 6-Chloro-3-iodo-1-(4-methoxybenzyl)-1H-
pyrrolo[2,3-b]pyridine (1a
Yield = 250 mg (88%); white color solid; mp = 87-88 °C;
1H NMR (500 MHz, CDCl3) δ (ppm): 7.59 (d,
= 8.2 Hz,
1H), 7.18 (d, = 8.5 Hz, 2H), 7.15 (s, 1H), 7.11 (d, = 8.2
Hz, 1H), 6.82 (d,
)
J
J
J
4.1.10.
3-Iodo-1-(4-methoxybenzyl)-5-(p-tolylethynyl)-
J
= 8.5 Hz, 2H), 5.32 (s, 2H), 3.75 (s, 3H).
1H-pyrrolo[2,3-b]pyridine (1f
)
13C{H} NMR (125 MHz, CDCl3) δ (ppm): 159.4, 146.1,
145.8, 131.9, 131.6, 129.5, 128.5, 121.7, 116.9, 114.2, 55.3,
54.0, 47.7. HRMS calcd. for C15H13ClIN2O(M+H+):
398.9761. found: 398.9771.
Yield = 239.7 mg (74%); bright yellow solid; mp = 134-
1
135 °C; H NMR (500 MHz, CDCl3) δ (ppm): 8.54 (s, 1H),
7.90 (s, 1H), 7.49 (d,
6.88 (d,
J = 7.7 Hz, 2H), 7.24-7.20 (m, 5H),
J
= 8.2 Hz, 2H), 5.42 (s, 2H), 3.81 (s, 3H), 2.41(s,
4.1.5. 3-Iodo-6-methoxy-1-(4-methoxybenzyl)-
3H). 13C{H} NMR (125 MHz, CDCl3) δ (ppm): 159.4,
147.0, 146.2, 138.4, 132.6, 132.0, 131.4, 129.3, 129.2,
128.7, 122.6, 120.1, 114.2, 113.3, 90.5, 86.7, 55.3, 54.0,
47.7, 21.5. HRMS calcd. for C24H20IN2O(M+H+): 479.0620.
found : 479.0641.
1H-pyrrolo[2,3-b]pyridine (1d
Yield = 203 mg (72%); white color solid; mp = 80-81 °C;
1H NMR (500 MHz, CDCl3) δ (ppm): 7.58 (d,
= 8.5 Hz,
1H), 7.25 (d, = 8.5 Hz, 2H), 7.06 (s, 1H), 6.87 (d,
8.5Hz, 2H), 6.64 (d,
)
J
J
J =
J
= 8.4 Hz, 1H), 5.32 (s, 2H), 4.03(s,
3H), 3.81 (s, 3H). 13C{H} NMR (125 MHz, CDCl3) δ (ppm):
161.6, 159.2, 144.8, 131.9, 129.5, 129.3, 128.3, 116.9,
114.0, 104.9, 55.3, 53.8, 53.5, 47.5. HRMS calcd. for
C16H16IN2O2 (M+H+): 395.0256. found : 395.0280.
4.1.11.
4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-
pyrrolo[2,3-b]pyridine (1g
)
Yield = 185 mg (65%); white color solid; mp = 107-108
1
°C; H NMR (500 MHz, CDCl3) δ (ppm): 8.23 (d,
J = 5.1
Hz, 1H), 7.31 (s, 1H), 7.21 (d, = 8.6 Hz, 2H), 7.11 (d,
J
J =
4.1.6. 5-Bromo-1-(4-methoxybenzyl)-1H-
5.1 Hz, 1H), 6.88-6.87 (m, 2H), 5.40 (s, 2H), 3.81 (s, 3H).
13C{H} NMR (125 MHz, CDCl3) δ (ppm): 1C is less we
observed. 159.4, 147.6, 143.6, 136.9, 133.9, 129.3, 128.5,
117.6, 114.2, 55.3, 49.0, 47.9. HRMS calcd. for
C15H13ClIN2O(M+H+): 398.9761. found : 398.9777.
pyrrolo[2,3-b]pyridine(5a
)
1
Yield = 228.6 mg (90%); colorless liquid; H NMR (500
MHz, CDCl3) δ (ppm): 8.39 (d, = 2.0 Hz, 1H), 8.04 (d,
2.05 Hz, 1H), 7.20-7.18 (m, 3H, 1peak extra of CDCl3),
J
J =
6.86 (d,
J = 8.6 Hz, 2H), 6.41 (d, J = 3.5 Hz, 1H), 5.40 (s,
2H), 3.79 (s, 3H). 13C{H} NMR (125 MHz, CDCl3) δ (ppm):
159.2, 145.9, 143.4, 130.7, 129.3, 129.2, 129.0, 122.0,
114.1, 111.6, 99.5, 55.2, 47.5. HRMS calcd. for
C15H14BrN2O(M+H+): 317.0290. found : 317.0267.
4.1.12.
4-iodo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridine (1h
)
Yield = 195 mg (72%); white color solid; mp = 71-72
1
°C; H NMR (500 MHz, CDCl3) δ (ppm): 7.99 (d,
Hz, 1H), 7.50 (d, = 5.0 Hz, 1H), 7.24 (d, = 3.4 Hz, 1H),
7.19 (d, = 8.45 Hz, 2H), 6.86 (d, = 8.4 Hz, 2H), 6.37 (d,
= 3.4 Hz, 1H), 5.41 (s, 2H), 3.79 (s, 3H). 13C{H} NMR
J = 5.0
J
J
4.1.7. 1-(4-methoxybenzyl)-5-(4-methoxy
phenyl)-1H-pyrrolo[2,3-b]pyridine(6a
J
J
)
J
Yield = 177.6 mg (95%); pale yellow solid; mp = 86-87
(125 MHz, CDCl3) δ (ppm): 1C is less we observed. 159.2,
145.6 142.8, 129.3, 129.0, 128.1, 125.2, 114.1, 103.1, 98.9,
55.2, 47.8. HRMS calcd. for C15H14IN2O(M+H+): 365.0151.
found : 365.0137.
1
°C; H NMR (500 MHz, CDCl3) δ (ppm): 8.58 (d,
Hz, 1H), 8.08 (d, = 2.0 Hz, 1H), 7.24-7.22 (m, 3H,), 7.05
(d, = 8.6 Hz, 2H), 6.87 (d, = 8.6 Hz, 2H), 6.54 (d, = 3.4
J = 1.9
J
J
J
J
Hz, 1H), 5.48 (s, 2H), 3.89 (s, 3H), 3.80 (s, 3H). 13C{H}
NMR (125 MHz, CDCl3) δ (ppm): 159.1, 158.9, 146.8,
142.1, 132.2, 129.8, 129.3, 128.9, 128.5, 128.4, 126.9,
120.6, 114.4, 114.1, 100.1, 55.3, 55.2, 47.4. HRMS calcd.
for C22H21N2O2 (M+H+): 345.1603. found: 345.1625.
4.1.13.
1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-1H-
pyrrolo[2,3-b]pyridine (
7)
Yield = 184 mg (74%); white color solid; mp = 127-128
1
°C; H NMR (500 MHz, CDCl3) δ (ppm): 8.31 (dd,
1.9 Hz, 1H), 7.89 (dd, = 9.7, 2.0 Hz, 1H), 7.32-7.30 (m,
2H), 7.07 (dd, = 9.7, 5.9 Hz, 1H), 6.92-6.89 (m, 4H),
J = 5.9,
J
4.1.8. 1-(4-methoxybenzyl)-5-(p-tolylethynyl)-
1H-pyrrolo[2,3-b]pyridine (6b
)
J
6.73-6.71 (m, 2H), 6.47 (s, 1H), 5.47 (s, 2H), 3.83 (s, 3H),
3.72 (s, 3H). 13C{H} NMR (125 MHz, CDCl3) δ (ppm):
159.7, 158.5, 149.1, 142.7, 141.7, 130.7, 130.6, 127.9,
127.8, 124.8, 120.7, 116.3, 113.9, 113.8, 99.6, 55.3, 55.2,
45.3. HRMS calcd. for C22H21N2O2(M+H+): 345.1603. found
: 345.1603.
Yield = 129 mg (66%); pale yellow color solid; mp = 120-
1
121 °C; H NMR (500 MHz, CDCl3) δ (ppm): 8.53 (d,
1.7 Hz, 1H), 8.09 (d, = 1.8 Hz, 1H), 7.48 (d, =8.0 Hz,
2H), 7.21-7.18 (m, 5H), 6.86 (d, = 8.6 Hz, 2H), 6.47 (d,
J =
J
J
J
J
= 3.5 Hz, 1H), 5.44 (s, 2H), 3.80 (s, 3H), 2.40 (s, 3H).
13C{H} NMR (125 MHz, CDCl3) δ (ppm): 159.1, 146.5,
146.0, 138.2, 131.6, 131.4, 129.4, 129.1, 129.0, 128.7,
120.3, 119.9, 114.1, 112.1, 100.2, 89.7, 87.3, 55.2, 47.4,
21.5. HRMS calcd. for C24H21N2O (M+H+): 353.1654. found
: 353.1669.
4.1.14.
3-iodo-1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-
1H-pyrrolo[2,3-b]pyridine(1i
)
Yield = 305 mg (95%); white color solid; mp = 142-143 °C;
1H NMR (500 MHz, CDCl3) δ (ppm): 8.39 (d,
1H), 7.77 (d,
= 7.8, 4.7 Hz, 1H), 6.99 (d,
Hz, 2H), 6.71 (d,
J
= 4.6 Hz,
4.1.9. 3-iodo-1-(4-methoxybenzyl)-5-(4-methoxyphenyl)-
J
= 7.8 Hz, 1H), 7.28-7.27 (m, 2H), 7.20 (dd,
J
1H-pyrrolo[2,3-b]pyridine (1e
)
J
= 8.4 Hz, 2H), 6.86 (d,
= 8.4 Hz, 2H), 5.44 (s, 2H), 3.90 (s, 3H),
J
= 8.4
J

9
3.75 (s, 3H). 13C{H} NMR (125 MHz, CDCl3) δ (ppm): 1C
is less we observed. 160.1, 158.6, 148.5, 144.0, 142.0,
132.1, 130.2, 129.0, 128.3, 123.5, 123.4, 117.1, 113.8,
1C), 129.8, 127.8, 127.0, 126.98-126.93 (m, 1C), 126.3-
126.2 (m, 1C), 122.4 (d, = 271.4 Hz, 1C), 119.1, 116.8,
J
114.5, 112.2, 55.3, 48.5.IR νmax (KBr): 3119, 3072, 2843,
1515, 1359, 1309 (SO2), 1277, 1179, 1145 (SO2), 1106,
1089, 630, 620. HRMS calcd. for C23H17F6N2O3S (M+H+)
:515.0864. found : 515.0864.
113.7,
55.3,
55.2,
46.1.
HRMS
calcd.
for
C22H19IN2O2(M+H+): 471.0569 found : 471.0581.
4.2.1. General procedure for the synthesis of C3 arylated
pyrrolo[2,3-b]pyridine and its derivatives.
4.2.5. 1-(4-methoxybenzyl)-3-(naphtalen-1-ylsulfonyl)-1H-
pyrrolo[2,3-b]pyridine (4d)
To a sealed tube containing dry DMF, catalyst and ligand
20 mol % each were added under nitrogen atmosphere. After
stirring the reaction mixture for 5 minutes at room
1
Yield = 137mg (64%), white solid, mp = 124-125 °C, H
NMR (500 MHz, CDCl3) δ (ppm): 8.46-8.44 (m, 2H), 7.88-
7.85 (m, 2H), 7.62-7.59 (m, 2H), 7.57-7.55 (m, 1H), 7.53 (s,
1H), 7.29-7.28 (m, 2H), 7.20 (t,
= 7.8, 4.7 Hz, 1H), 6.94 (dd,
temperature, 3-iodo-1-(4-methoxybenzyl)-1
H-pyrazolo[2,3-
J
= 7.6 Hz, 1H), 7.12 (dd,
= 7.35, 0.9 Hz, 2H), 6.91-
J
b
]pyridine (0.5 mmol), aryl boronic acid (1.2 equiv., 0.6
1
J
mmol) and DABSO (1.5 equiv., 0.75 mmol) were added.
The reaction mixture was heated at 100°C in the heating
bath under nitrogen atmosphere. When the TLC indicated
the total consumption of starting material, the reaction
mixture was allowed to cool at ambient temperature. The
reaction mixture was quenched with 10 mL of cold water
and was extracted with ethyl acetate (50 mL X 3). Organic
layer was washed with brine. The combined organic layers
were dried over Na2SO4 and concentrated under reduced
pressure. The resulting residue was purified by column
chromatography (silica gel, hexane/EtOAc) to give the
6.89 (m, 2H), 5.52 (s, 2H), 3.82 (s, 3H).13C{H} NMR (125
MHz, CDCl3) δ (ppm): 159.3, 148.3, 144.0, 135.9, 134.1,
133.7, 130.7, 129.3, 128.9, 128.4, 128.0, 126.2, 126.1,
125.6, 125.5, 123.9, 123.5, 122.1, 116.8, 114.2, 99.7, 55.3,
47.7.IR νmax (KBr): 2983, 2931, 2803, 1510, 1414, 1300
(SO2), 1251, 1173, 1161 (SO2), 1032, 793, 767, 550.
MALDI-TOF calcd. for C25H20LiN2O3S (M+Li+): 435.1355.
found : 435.0511.
4.2.6.
benzyl)-1H-pyrrolo
3-((4,6-dihydropyren-1-yl)sulfonyl)-1-(4-methoxy
2,3-b]pyridine (4e
[
)
desired products (4a-4zf).
1
Yield= 88 mg (35%), yellow solid, mp = 118-119 °C, H
NMR (500 MHz, CDCl3) δ (ppm): 8.72 (d, = 9.1 Hz, 1H),
8.44 (dd, = 4.7, 1.4 Hz, 1H), 8.23-8.17 (m, 3H), 8.04-8.00
(m, 2H), 7.95 (d, = 8.9 Hz, 1H), 7.89 (d, = 8.1 Hz, 1H),
7.85 (dd, = 7.8, 1.4 Hz, 1H),7.86 (s, 1H), 7.56 (d, = 8.1
Hz, 1H), 7.30 (d, = 8.6 Hz, 2H), 7.08 (dd, = 7.8, 4.7 Hz,
J
4.2.2. 1-(4-methoxybenzyl)-3-((4-methoxyphenyl) sulfonyl)-
1H-pyrrolo[2,3-b]pyridine (4a
J
)
J
J
J
J
Yield : 110 mg (54%); Peach color solid; mp 122-123 °C;
1H NMR (500 MHz, CDCl3) δ (ppm): 8.45-8.44 (m, 1H),
J
J
1H), 6.91-6.90 (m 2H), 5.53 (s, 2H), 3.82 (s, 3H), 3.74 (s,
3H).13C{H} NMR (125 MHz, CDCl3) δ(ppm): 159.3,148.4,
144.0, 133.9, 133.2, 131.5, 131.1, 129.3, 129.1, 129.0,
128.0, 127.6, 127.3, 126.7, 126.1, 125.1, 125.0, 124.9,
124.9, 124.6, 123.3, 122.1, 116.9, 114.2, 100.6, 55.3,
47.7.IR νmax (KBr): 3118, 2988, 2948, 1507, 1414, 1289
(SO2), 1246, 1178, 1159 (SO2), 1030, 843, 768, 711.
MALDI-TOF calcd. for C31H25N2O3S (M+H+): 505.1586.
found : 506.1168.
8.21 (dd,
(s, 1H), 7.26-7.23 (m, 3H), 6.94 (d,
J
= 7.9, 1.4 Hz, 1H), 7.92 (d,
J = 8.9 Hz, 2H), 7.84
J
= 8.8 Hz, 2H), 6.88 (d,
J
= 8.5 Hz, 2H), 5.43 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H).
13C{H} NMR (125 MHz, CDCl3) δ (ppm): 162.9, 159.6,
147.5, 144.8, 134.7, 131.7, 129.7, 128.9, 128.2, 127.6,
118.3, 116.8, 115.1, 114.4, 114.3, 55.6, 55.3, 48.1. IR νmax
(KBr): 3096, 2940, 2837, 1595, 1514, 1496, 1394, 1295
(SO2), 1258, 1143 (SO2), 1081, 1027, 676, 584. HRMS
calcd. for C22H21N2O4S (M+H+): 409.1222. found: 409.1218.
4.2.7.
5-bromo-1-(4-methoxybenzyl)-3-(pyridin-4-
4.2.3.-1-(4-methoxybenzyl)-3-tosyl
b]pyridine (4b
-1H-pyrrolo[2,3-
ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(4f
)
)
Yield= 123 mg (54%); peach color solid; mp = 135-136
°C;1H NMR (500 MHz, CDCl3) δ (ppm): 8.82 (dd,
= 4.4,
1.5 Hz, 2H), 8.51 (d, = 2.1 Hz, 1H), 8.38 (d, = 2.1 Hz,
1H), 7.87 (s, 1H), 7.78 (dd, = 4.3, 1.6 Hz, 2H), 7.28-7.25
(m, 2H), 6.89 (dd, = 8.5, 1.8 Hz, 2H), 5.41 (s, 2H), 3.82 (s,
Yield= 117.6 mg (60%); light yellow solid; mp = 126-127
°C;1H NMR (500 MHz, CDCl3) δ(ppm): 8.44 (dd,
= 4.7,
1.5 Hz, 1H), 8.23 (dd, = 8.0, 1.5 Hz, 1H), 7.87 (d, =8.3
J
J
J
J
J
J
J
Hz, 2H), 7.85 (s, 1H), 7.28-7.25 (m, 6H, one peak of
CDCl3), 6.90-6.88 (m, 2H), 5.43 (s, 2H), 3.82 (s, 3H),
2.38(s, 3H). 13C{H} NMR (125 MHz, CDCl3) δ(ppm):
159.6, 147.5, 144.9, 143.6, 140.1, 132.0, 129.7, 129.7,
128.3, 127.5, 126.7, 118.4, 116.9, 114.7, 114.4, 55.3, 48.2,
21.5.IR νmax (KBr): 3101, 2937, 2837, 1515, 1392, 1330
(SO2), 1243, 1145 (SO2), 1080, 1025, 673, 576. HRMS
calcd. for C22H21N2O3S (M+H+).: 393.1273. found:
393.1266.
J
3H). 13C{H} NMR (125 MHz, CDCl3) δ (ppm): we observed
one carbon peak less in spectra, 159.9, 151.2, 146.3, 145.9,
134.1, 130.2, 129.8, 126.7, 119.6, 118.3, 115.2, 114.6,
112.0, 55.3, 48.7. IR νmax (KBr): 3143, 3036, 2930, 2831,
1513, 1397, 1322 (SO2), 1245, 1171, 1146 (SO2), 1090,
1028, 808, 725, 619, 597. HRMS calcd. for C20H17BrN3O3S
(M+H+): 458.0174. found : 458.0192.
4.2.8.
5-bromo-1-(4-methoxybenzyl)-3-(thiophen-3-
4.2.4.
methoxybenzyl)
3-(3,5(bis(trifluoromethyl)phenyl)sulfonyl)-1-(4-
1H-pyrrolo[2,3-b]pyridine (4c
ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(4g
)
-
)
Yield = 64 mg (28%); light orange solid; mp = 164-165
Yield= 115.6 m (45%); peach color solid; mp = 169-170
°C;1H NMR (500 MHz, CDCl3) δ (ppm): 8.51 (dd,
= 4.6,
1.1 Hz, 1H), 8.42 (s, 2H), 8.25 (dd, = 7.9, 1.2 Hz, 1H),
8.02 (s, 1H), 7.93 (s, 1H), 7.34 (dd, =8.0, 4.7 Hz, 1H), 7.27
(d, = 8.2 Hz, 2H), 6.91 (d, =8.6 Hz, 2H), 5.48 (s, 2H),
3.83 (s, 3H). 13C{H} NMR (125 MHz, CDCl3) δ(ppm):
159.8, 147.6, 145.9, 145.5, 133.3, 132.9 (q, = 34.3 Hz,
°C;1H NMR (500 MHz, CDCl3) δ (ppm): 8.47 (dd,
1.5 Hz, 1H), 8.24 (dd, = 7.9, 1.5 Hz, 1H), 8.10 (dd,
J
= 4.7,
J
J
J = 2.6,
J
1.8 Hz, 1H), 7.86 (s, 1H), 7.35-7.34 (m, 2H), 7.28-7.26 (m,
J
3H, one peak of CDCl3), 6.89 (d,
J = 8.6 Hz, 2H), 5.45 (s,
J
J
2H), 3.82 (s, 3H). 13C{H} NMR (125 MHz, CDCl3) δ (ppm):
159.7, 149.0, 147.5, 145.0, 143.7, 132.1, 130.1, 129.7,
128.2, 128.1, 127.4, 125.3, 118.5, 116.9, 114.4, 55.3,
J

10
Tetrahedron
48.2.IR νmax (KBr): 3112, 2959, 2933, 1512, 1416, 1389,
Yield= 111.8 mg (52%); off white solid; mp = 144-145
°C;1H NMR (500 MHz, CDCl3) δ (ppm): 8.16-8.15 (m, 1H),
7.99-7.96 (m, 2H), 7.78 (s, 1H), 7.28-7.26 (m, 3H), 7.16-
7.14 (m, 3H, one peak extra due to CDCl3), 6.91-6.89 (m,
2H), 5.38 (s, 2H), 3.83 (s, 3H). 13C{H} NMR (125 MHz,
1305 (SO2), 1243, 1164, 1145 (SO2), 1088, 1029, 785, 771,
658, 630, 612. HRMS calcd. for C19H17BrN2O3S2(M+H+)
:462.9786. found: 462.9806.
4.2.9.
5-bromo-1-(4-methoxybenzyl)-3-(naphthalene-2-
CDCl3) δ(ppm): 165.2 (d,
146.5, 138.8 (d, = 3.1 Hz, 1C), 132.1, 130.5, 130.0, 129.5
(d, = 9.4 Hz, 1C), 126.8, 119.1, 116.5 (d, = 22.5 Hz, 1C),
J = 253.9 Hz, 1C), 159.8, 146.9,
ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(4h
)
J
J
J
Yield= 170.6 mg (68%); light yellow solid; mp = 186-187
°C;1H NMR (500 MHz, CDCl3) δ (ppm): 8.63-8.59 (m, 2H),
115.3, 114.9, 114.5, 55.3, 48.5, 30.6 (acetone).IR νmax (KBr):
3115, 3079, 2948, 2831, 1612, 1589, 1515, 1315(SO2),
1289, 1251, 1148(SO2), 1078, 1033, 837, 816, 676, 591,
529. HRMS calcd. for C21H17ClFN2O3S (M+H+): 431.0632.
found: 431.0636.
8.46 (d,
(m, 4H), 7.65-7.60 (m, 2H), 7.24 (d,
(d,
= 7.9 Hz, 2H), 5.39 (s, 2H), 3.81 (s, 3H). 13C{H} NMR
(125 MHz, CDCl3) δ(ppm): 159.7, 150.5, 145.8, 139.5,
136.1, 134.9, 133.3, 132.2, 130.4, 129.7, 129.7, 129.4,
129.0, 127.9, 127.8, 127.6, 122.0, 118.3, 114.7, 114.5,
114.0, 55.3, 48.5.IR νmax (KBr): 3086, 2950, 2926, 1510,
1394, 1307 (SO2), 1298, 1249, 1169, 1145 (SO2), 1128,
1072, 805, 681, 655, 641. HRMS calcd.for
C25H20BrN2O3S(M+H+): 507.0378. found : 507.0392.
J
= 3.6 Hz, 1H), 8.00 (d,
J
= 7.7 Hz, 1H), 7.93-7.86
J
= 8.4 Hz, 2H), 6.88
J
4.2.14.
6-chloro-1-(4-methoxybenzyl)-3-((4-trifluoro
methoxy)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (4m
Yield= 114 mg (46%); white solid; mp = 114-115 °C;1H
NMR (500 MHz, CDCl3) δ (ppm): 8.18 (d, = 8.3 Hz, 1H),
8.01 (d,
6.91 (d,
NMR (125 MHz, CDCl3) We are getting one less carbon
peak here δ(ppm): 159.9, 152.2, 147.0, 146.5, 141.0, 132.3,
130.5, 130.0, 128.9, 126.7, 121.0, 119.2, 115.4, 114.5,
114.4, 55.3, 48.5. IR νmax (KBr): 3076, 2966, 2846, 1514,
1324 (SO2), 1263, 1214, 1159, 1149 (SO2), 1080, 1033, 808,
629, 596. HRMS calcd. for C22H17ClF3N2O4S (M+H+) :
497.0550. found : 497.0568.
)
J
J
J
= 8.8 Hz, 2H), 7.79 (s, 1H), 7.32-7.27 (m, 5H),
= 8.6 Hz, 2H), 5.39 (s, 2H), 3.83 (s, 3H).13C{H}
4.2.10. 3-(anthracen-2-ylsulfonyl)-5-bromo-1-(4-methoxy
benzyl)-1H-pyrrolo[2,3-b]pyridine (4i)
Yield = 196mg (71%), light yellow solid, mp = 210-211
°C, 1H NMR (500 MHz, CDCl3) δ (ppm): 8.80 (s, 1H), 8.66-
8.61 (m, 1H), 8.47-8.43 (m, 3H), 8.06-8.04 (m, 3H), 7.93-
7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.57 (s, 2H), 7.28-7.24 (m,
2H), 6.90-6.88 (m, 2H), 5.40 (s, 2H), 3.81 (s, 3H).13C{H}
NMR (125 MHz, CDCl3) δ (ppm): 159.8, 145.9, 138.7,
133.4, 133.3, 132.4, 131.7, 130.4, 130.2, 129.7, 129.6,
129.0, 128.9, 128.4, 128.2, 127.0, 126.6, 126.4, 120.6,
118.4, 114.8, 114.5, 113.9, 55.3, 48.5, 29.7 (acetone).IR νmax
(KBr): 2923, 1511, 1314 (SO2), 1249, 1171, 1136 (SO2),
828, 721, 642. 623, 556. MALDI-TOF calcd. for
C29H22BrN2O3S (M+H+): 557.0535. found : 557.0112.
4.2.15. (E)-6-chloro-1-(4-methoxybenzyl)-3-((4-methoxy
styryl)sulfonyl)-1H-pyrrolo[2,3-b]pyridine (4n)
Yield = 98 mg (42%); white solid; mp = 169-170 °C;1H
NMR (500 MHz, CDCl3) δ(ppm): 8.16 (d,
7.75 (s, 1H), 7.65 (d, = 15.2 Hz, 1H), 7.42 (d,
2H), 7.29 (dd, = 11.2, 8.6 Hz, 3H), 6.92-6.88 (m, 4H), 6.76
(d, = 15.2 Hz, 1H), 5.40 (s, 2H), 3.84 (s, 3H), 3.82 (s,
J
= 8.3 Hz, 1H),
J
J
= 8.8 Hz,
J
4.2.11.
6-chloro-1-(4-methoxybenzyl)-3-(phenylsulfonyl)-
J
1H-pyrrolo[2,3-b]pyridine(4j
)
:
3H).13C{H} NMR (125 MHz, CDCl3) δ(ppm): 161.9, 159.8,
146.7, 146.5, 140.8, 132.1, 130.6, 130.2, 130.1, 127.0,
125.6, 124.9, 118.8, 115.5, 114.5, 114.4, 114.4, 55.4, 55.3,
48.4. IR νmax (KBr): 3135, 3052, 2949, 2833, 1601, 1513,
1305 (SO2), 1287, 1259, 1159 (SO2), 1110, 838, 628, 592.
HRMS calcd. for C24H22ClN2O4S: 469.0989. found:
469.0998.
Yield= 160.6 mg (78%); light brown solid; mp = 132-133
°C;1H NMR (500 MHz, CDCl3) δ(ppm): 8.16 (d,
= 8.4 Hz,
1H), 7.95 (d, = 7.5 Hz, 2H), 7.77 (s, 1H), 7.53 (t, = 7.3
Hz, 1H), 7.48-7.47 (m, 2H),7.25 (d, = 8.3 Hz, 3H), 6.89 (d,
= 8.5 Hz, 2H), 5.36 (s, 2H), 3.81 (s, 3H). 13C{H} NMR
J
J
J
J
J
(125 MHz, CDCl3) δ(ppm): 159.8, 146.7, 146.5, 142.7,
132.9, 132.1, 130.6, 130.0, 129.2, 126.8, 126.7, 119.0,
115.5, 115.0, 114.5, 55.3, 48.4.IR νmax (KBr): 3116, 2949,
2923, 1515, 1409, 1303 (SO2), 1250, 1162, 1147 (SO2),
1078, 1031, 725, 621, 594. HRMS calcd. for C21H18ClN2O3S
(M+H+): 413.0727. found : 413.0748.
4.2.16. 4-((4-chloro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridin-3-yl)sulfonyl)benzonitrile (4o
Yield= 76 mg (35%); white solid; mp = 172-173 °C;1H
)
NMR (500 MHz, CDCl3) δ(ppm): 8.34 (d, = 5.1 Hz, 1H),
8.1.8 (s, 1H), 8.05 (d, = 8.5 Hz, 2H),7.78 (d, = 8.4 Hz,
2H), 7.31-7.28 (m, 3H, one extra peak due to CDCl3), 7.23
(d, = 5.1 Hz, 1H), 6.92 (d, J =8.5 Hz, 2H), 5.48 (s, 2H),
J
J
J
4.2.12.
6-chloro-1-(4-methoxybenzyl)-3-(m-tolylsulfonyl)-
1H-pyrrolo[2,3-b]pyridine (4k
)
J
3.83 (s, 3H).13C{H} NMR (125 MHz, CDCl3) δ(ppm):
159.9, 149.2, 146.9, 145.4, 136.4, 136.1, 132.7, 129.8,
128.2, 126.8, 119.9, 117.3, 116.3, 115.1, 114.6, 112.6, 55.3,
48.9.IR νmax (KBr): 3117, 2957, 2928, 2831, 2230, 1514,
1388, 1303 (SO2), 1249, 1167, 1143 (SO2), 831, 647, 599.
HRMS calcd. for C22H17ClN3O3S(M+H+): 438.0679. found :
438.0685.
Yield= 121 mg (57%); light brown solid; mp = 91-92 °C;1H
NMR (500 MHz, CDCl3) δ(ppm): 8.17 (d, = 8.3 Hz, 1H),
7.819-7.815 (m, 1H), 7.77-7.76 (m, 2H), 7.38-7.32 (m,
2H),7.28-7.25 (m, 3H), 6.89 (d, = 8.5 Hz, 2H), 5.38 (s,
J
J
2H), 3.81 (s, 3H), 2.39 (s, 3H). 13C{H} NMR (125 MHz,
CDCl3) δ(ppm): 159.8, 149.0, 146.7, 146.5, 142.6, 139.5,
133.7, 132.1, 130.6, 129.9, 129.1, 127.0, 123.8, 118.9,
115.5, 115.1, 114.5, 55.3, 48.4, 21.3.IR νmax (KBr): 3135,
3017, 2963, 2839, 1514, 1411, 1384, 1303 (SO2), 1246,
1162, 1145 (SO2), 1117, 1077, 1032, 768, 699, 630, 601.
HRMS calcd. for C22H20ClN2O3S (M+H+): 427.0883. found
: 427.0887.
4.2.17. 6-methoxy-1-(4-methoxybenzyl)-3-(phenylsulfonyl)-
1H-pyrrolo[2,3-b]pyridine (4p
)
Yield= 91.8 mg (45%); peach color solid; mp = 144-145
°C;1H NMR (500 MHz, CDCl3) δ(ppm): 8.07(d,
= 8.6 Hz,
J
1H), 7.98-7.97 (m, 2H), 7.67 (s, 1H), 7.54 -7.50 (m, 1H),
7.49-7.45 (m, 2H), 7.29-7.27 (m, 2H), 6.90-6.87 (m, 2H),
6.72 (d, J =8.6 Hz, 1H), 5.33 (s, 2H), 4.00 (s, 3H), 3.82 (s,
4.2.13.
6-chloro-3-((4-fluorophenyl)sulfonyl)-1-(4-
methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine (4l
)

11
3H).13C{H} NMR (125 MHz, CDCl3) δ(ppm): 161.9, 159.6,
145.4, 143.2, 132.5, 130.8, 129.7, 129.0, 128.9, 127.9,
126.6, 114.7, 114.3, 110.6, 107.1, 55.3, 53.6, 48.3.IR νmax
(KBr): 3125, 3005, 2977, 2942, 2839, 1604, 1511, 1413,
1302 (SO2), 1270, 1242, 1147 (SO2), 1026, 722, 591. HRMS
calcd. for C22H21N2O4S (M+H+): 409.1222. found: 409.1221.
816, 642, 584. HRMS calcd. for C23H23N2O4S2(M+H+):
455.1099. found : 455.1098.
4.2.22. 4-((6-methoxy-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridin-3-yl)sulfonyl)benzonitrile (4u
)
1
Yield = 127.7 mg (59%); white solid; mp = 185-186 °C; H
NMR (500 MHz, CDCl3) δ(ppm): 8.07-8.04 (m, 3H), 7.77-
7.75 (m, 2H), 7.68 (s, 1H), 7.29-7.27 (m, 2H), 6.90-6.88 (m,
4.2.18.
3-((4-fluorophenyl)sulfonyl)-6-methoxy-1-(4-
methoxy benzyl)-1H-pyrrolo[2,3-b]pyridine (4q
)
2H), 6.75 (d,
J = 8.6 Hz, 1H), 5.34 (s, 2H), 4.01 (s, 3H), 3.82
Yield = 142.7 mg (67%); off white solid; mp = 173-174 °C;
1H NMR (500 MHz, CDCl3) δ(ppm): 8.04 (d,
= 8.6 Hz,
1H), 7.98 (dd, = 8.6, 5.1 Hz, 2H), 7.66 (s, 1H), 7.29-7.27
(m, 2H), 7.14 (t, = 8.5 Hz, 2H), 6.88 (d, = 8.4 Hz, 2H),
6.73 (d, = 8.6 Hz, 1H), 5.33 (s, 2H), 4.00 (s, 3H), 3.81 (s,
3H). 13C{H} NMR (125 MHz, CDCl3) δ(ppm): 165.0 (d,
253.1 Hz, 1C), 161.9, 159.6, 145.4, 139.4 (d, = 3.1 Hz,
1C), 130.6, 129.7, 129.3 (d, = 9.3 Hz, 1C), 128.9, 127.8,
116.3 (d, = 22.4 Hz, 1C), 114.5, 114.3, 110.5, 107.3, 55.3,
(s, 3H).13C{H} NMR (125 MHz, CDCl3) δ(ppm): 162.1,
159.7, 147.4, 145.5, 132.9, 130.5, 129.8, 129.6, 127.5, 127.2,
117.3, 116.2, 114.3, 113.1, 110.5, 107.7, 55.3, 53.7, 48.6.IR
νmax (KBr): 3124, 2955, 2840, 2230, 1604, 1514, 1410, 1299
(SO2), 1274, 1248, 1145 (SO2), 1031, 822, 663, 560. HRMS
calcd.for C23H20N3O4S(M+H+). :434.1175. found: 434.1175.
J
J
J
J
J
J
=
J
4.2.23. 6-methoxy-1-(4-methoxybenzyl)-3-((3,4,5-trimethoxy
J
phenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridine (4v
)
J
yield = 159 mg (64%);White solid; mp = 175-176 °C;1H
53.6, 48.3. IR νmax (KBr): 3143, 3036, 2930, 2833, 1513,
1397, 1322 (SO2), 1245, 1171, 1146 (SO2), 1090, 1028, 808,
619, 597. HRMS calcd. for C22H20FN2O4S(M+H+)
:427.1128. found : 427.1120.
NMR (500 MHz, CDCl3) δ (ppm): 8.08 (d, = 8.6 Hz, 1H),
7.66 (s, 1H), 7.27 (d, = 8.9 Hz, 2H), 7.18 (s, 2H), 6.87 (d,
= 8.6 Hz, 2H), 6.73 (d,
J
J
J
J
= 8.6 Hz, 1H), 5.34 (s, 2H), 4.00 (s,
3H), 3.86 (s, 6H), 3.85 (s, 3H), 3.81 (s, 3H).13C{H} NMR
(125 MHz, CDCl3) δ(ppm): 161.9, 159.6, 153.3, 145.4, 141.4,
138.0, 130.7, 129.7, 128.7, 128.0, 114.8, 114.2, 110.5, 107.2,
4.2.19.
6-methoxy-1-(4-methoxybenzyl)-3-((3-nitrophenyl)
sulfonyl)-1H-pyrrolo[2,3-b]pyridine (4r
)
Yield = 122 mg (54%); light orange solid; mp = 180-181 103.9, 60.9, 56.3, 55.3, 53.6, 48.2. IR νmax (KBr): 3116, 2947,
°C;1H NMR (500 MHz, CDCl3) δ (ppm): 8.06 (d,
= 8.6 Hz, 2836, 1600, 1515, 1496, 1413, 1307 (SO2), 1254, 1163, 1139
1H), 7.64 (s, 1H), 7.32-7.27 (m, 4H, one peak extra due to (SO2), 1123, 1011, 649, 629. HRMS calcd.for
CDCl3), 7.25 (t, = 2.0 Hz, 1H), 7.21 (t,
= 7.9 Hz, 1H), C25H27N2O7S(M+H+) : 499.1539. found : 499.1537.
6.89-6.86 (m, 2H), 6.78-6.76 (m, 1H), 6.71 (d, = 8.6 Hz,
J
J
J
J
4.2.24. 3-((6-methoxy-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridin-3-yl)sulfonyl)phenol (4w
1H), 5.32 (s, 2H), 4.00 (s, 3H), 3.81 (s, 3H).13C{H} NMR
(125 MHz, CDCl3) δ (ppm): 161.8, 159.5, 147.0, 145.3,
144.0, 130.9, 129.9, 129.7, 128.8, 127.9, 118.8, 116.3, 114.7,
114.2, 112.3, 110.7, 107.0, 55.3, 53.5, 48.2.IR νmax (KBr):
3446, 3360, 3248, 3094, 2952, 2837, 1602, 1513, 1441, 1409,
1293 (SO2), 1272, 1243, 1139 (SO2), 1023, 706, 644, 415.
HRMS calcd. for C22H20N3O6S(M+H+): 454.1072. found : not
observed.
)
Yield = 112 mg (53%); white solid; mp = 177-178 °C;1H
NMR (500 MHz, CDCl3) δ(ppm): 8.06 (s, 1H), 8.04 (d,
8.6 Hz, 1H), 8.02 (s, 1H, DMF), 7.65 (s, 1H), 7.53 (t, = 2.0
Hz, 1H),7.46-7.44 (m, 1H), 7.29-7.25 (m, 3H), 7.01 (dd,
7.4, 2.4 Hz, 1H), 6.87-6.85 (m, 2H), 6.68 (d, = 8.6 Hz, 1H),
5.30 (s, 2H), 3.98 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H, DMF),
2.91 (s, 3H, DMF).13C{H} NMR (125 MHz, CDCl3) δ(ppm):
162.0 (DMF), 161.8, 159.5 157.2, 145.4, 144.0, 130.8, 130.2,
129.7, 129.0, 127.9, 120.1, 118.0, 114.4, 114.2, 113.5, 110.6,
J
=
J
J
=
J
4.2.20. 3-((4-bromophenyl)sulfonyl)-6-methoxy-1-(4-methoxy
benzyl)-1H-pyrrolo[2,3-b]pyridine (4s
)
1
Yield = 124 mg (51%); white solid; mp = 123-124 °C; H 107.1, 55.3, 53.6, 48.2, 36.7 (DMF), 31.6 (DMF).IR νmax
NMR (500 MHz, CDCl3) δ(ppm): 8.04 (d, = 8.6 Hz, 1H), (KBr): 3340, 3102, 2928, 1602, 1514, 1443, 1411, 1306
7.83-7.81 (m, 2H), 7.68-7.59 (m, 3H), 7.29 – 7.27 (m, 2H), (SO2), 1270, 1137 (SO2), 706, 686, 623. HRMS calcd. for
6.89 (d, = 8.5 Hz, 2H), 6.73 (d,
= 8.6 Hz, 1H), 5.33 (s, C22H21N2O5S (M+H+): 425.1171. found : 425.1165.
J
J
J
2H), 4.00 (s, 3H), 3.81 (s, 3H). 13C{H} NMR (125 MHz,
CDCl3) δ(ppm): 162.0, 159.6, 145.4, 142.3, 138.3, 132.3,
130.6, 129.8, 129.0, 128.2, 128.1, 127.7, 114.3, 110.5, 107.4,
55.3, 53.6, 48.3.IR νmax (KBr): 3133, 3009, 2945, 2825, 1601,
1574, 1413, 1387, 1311 (SO2), 1272, 1249, 1147 (SO2), 1028,
818, 630, 586. HRMS calcd. for C22H20BrN2O4S (M+H+):
487.0327. found : 487.0341.
4.2.25 3-((6-methoxy-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridin-3-yl)sulfonyl)benzaldehyde (4x
)
Yield = 128.6 mg (59%); light orange solid; mp = 157-158
1
°C; H NMR (500 MHz, CDCl3) δ (ppm): 10.04 (s, 1H),
8.44 (s, 1H), 8.23 (d,
1H), 8.03 (d, = 7.5 Hz, 1H),7.71 (s, 1H), 7.66 (t,
Hz, 1H), 7.29 (d, = 8.0 Hz, 2H), 6.89 (d, = 8.2 Hz, 2H),
6.74 (d, = 8.6 Hz, 1H), 5.34 (s, 2H), 4.00 (s, 3H), 3.82 (s,
3H).13C{H} NMR (125 MHz, CDCl3) δ(ppm): 190.4, 162.0,
Yield = 129.4 mg (57%); light orange solid; mp = 132-133 159.6, 145.5, 144.8, 136.9, 132.9, 131.9, 130.6, 130.0,
°C; 1H NMR (500 MHz, CDCl3) δ (ppm): 8.05 (d,
= 8.6 Hz, 129.8, 129.4, 127.8, 127.7, 114.3, 113.7, 110.5, 107.5, 55.3,
1H), 7.85 (d, = 8.5 Hz, 2H), 7.64 (s, 1H), 7.26 (dd, = 10.6, 53.6, 48.2.IR νmax (KBr): 3129, 2951, 2834, 2734, 1705,
8.7 Hz, 5H, one peak of CDCl3 extra), 6.89 (d, = 8.6 Hz, 1513, 1389, 1307 (SO2), 1281, 1249, 1156, 1141 (SO2),
J
= 7.7 Hz, 1H), 8.07 (d,
J
= 8.6 Hz,
J
J
= 7.7
J
J
4.2.21.
6-methoxy-1-(4-methoxybenzyl)-3-(((4-methylthio)
J
phenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridine (4t
)
J
J
J
J
2H), 6.71 (d,
J
= 8.6 Hz, 1H), 5.32 (s, 2H), 4.00 (s, 3H), 3.81 1013, 820, 620, 601. HRMS calcd. for C23H21N2O5S (M+H+)
(s, 3H), 2.48 (s, 3H).13C{H} NMR (125 MHz, CDCl3) : 437.1171. found : 437.1170.
δ(ppm): 161.9, 159.5, 145.6, 145.4, 139.0, 130.7, 129.7,
4.2.26 3-(benzo[d][1,3]dioxol-5-ylsulfonyl)-6-methoxy-1-(4-
methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine (4y
128.6, 127.9, 127.0, 125.4, 115.0, 114.3, 110.5, 107.1, 55.3,
53.6, 48.2, 14.7.IR νmax (KBr): 3134, 3060, 2955, 1600, 1577,
1510, 1414, 1309 (SO2), 1273, 1245, 1148 (SO2), 1091, 1078,
)

12
Tetrahedron
Yield = 110 mg (49%); white solid; mp = 155-156 °C;1H
NMR (500 MHz, CDCl3) δ (ppm): 8.04 (d, = 8.6 Hz, 1H),
7.63 (s, 1H), 7.58 (dd, = 8.2, 1.8 Hz, 1H),7.35 (d, = 1.8
Hz, 1H), 7.29 (d, = 2.5 Hz, 1H), 7.27 (s, 1H), 6.88 (m,
Yield = 145 mg (55%); light orange solid; mp = 181-182
°C;1H NMR (500 MHz, CDCl3) δ(ppm): 8.64 (d,
= 1.9 Hz,
1H), 8.31 (d, = 1.9 Hz, 1H), 7.84 (s, 1H), 7.61 (dd, = 8.2,
1.5 Hz, 1H), 7.56 (d, = 8.6 Hz, 2H), 7.37 (d, = 1.5 Hz,
1H), 7.29-7.28 (m, 2H), 7.06 (d, = 8.6 Hz, 2H), 6.90 (d,
= 8.5 Hz, 2H), 6.85 (d, = 8.2 Hz, 1H), 6.03 (s, 2H), 5.45 (s,
J
J
J
J
J
J
J
J
J
2H), 6.85 (d, J =8.2 Hz, 1H), 6.72 (d, J =8.6 Hz, 1H), 6.03
(s, 2H), 5.32 (s, 2H), 4.00 (s, 3H), 3.82 (s, 3H).13C{H} NMR
(125 MHz, CDCl3) δ(ppm): (one carbon might be merged
here) 161.9, 159.5, 151.3, 148.1, 145.4, 136.7, 130.8, 129.7,
128.5, 127.9, 122.3, 115.1, 114.3, 110.5, 108.3, 107.1,
102.2, 55.3, 53.6, 48.2.IR νmax (KBr): 3125, 3066, 2904,
1514, 1480, 1414, 1307 (SO2), 1276, 1250, 1157 (SO2),
1105, 1035, 818, 706, 616, 522. HRMS calcd. for
C23H21N2O6S (M+H+): 453.1120. found: 453.1115.
J
J
J
2H), 3.90 (s, 3H), 3.83 (s, 3H). 13C{H} NMR (125 MHz,
CDCl3) δ(ppm): 159.7, 159.4, 151.4, 148.2, 146.7, 144.2,
136.5, 132.4, 132.1, 130.9, 129.7, 128.7, 127.5, 125.8,
122.4, 116.8, 114.7, 114.5, 114.4, 108.4, 107.0, 102.2, 55.4,
55.3, 48.3.IR νmax (KBr): 3100, 2962, 2831, 1609, 1512,
1482, 1312 (SO2), 1247, 1163, 1134 (SO2), 1034, 834, 620,
554. HRMS calcd. for C29H25N2O6S (M+H+): 529.1433.
found: 529.1456.
4.2.27 3-((2,3-dihyrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-6-
methoxy-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine
4.2.31
1-(4-methoxybenzyl)-4-tosyl-1H-pyrrolo[2,3-b]
(4z
)
pyridine (4zd)
Yield = 125.8 mg (54%); light orange solid; mp = 152-153
Yield = 98mg (50%); light yellow solid; mp = 130-131
°C;1H NMR (500 MHz, CDCl3) δ (ppm): 8.50 (d,
= 5.0
Hz, 1H), 7.93 (d, = 8.3 Hz, 2H), 7.67 (d, = 5.0 Hz, 1H),
7.37 (d, = 3.6 Hz, 1H), 7.30-7.28 (m, 2H), 7.20-7.18 (m,
2H), 6.95 (d, = 3.5 Hz, 1H), 6.86-6.83 (m, 2H), 5.45 (s,
1
°C; H NMR (500 MHz, CDCl3) δ (ppm): 8.05 (d,
Hz, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.46 (d, = 2.0 Hz, 1H),
7.28 (d, = 8.1 Hz, 2H), 6.92-6.87 (m, 3H), 6.71 (d, = 8.6
J
= 8.6
J
J
J
J
J
J
J
Hz, 1H), 5.31 (s, 2H), 4.27- 4.24 (m, 4H), 3.99 (s, 3H), 3.81
(s, 3H).13C{H} NMR (125 MHz, CDCl3) δ(ppm): 161.8,
159.5, 147.3, 145.4, 143.5, 135.8, 130.8, 129.7, 128.5,
127.9, 120.4, 117.8, 116.3, 115.2, 114.3, 110.5, 107.0, 64.4,
64.1, 55.3, 53.6, 48.2.IR νmax (KBr): 3115, 2936, 2884,
2840, 1605, 1516, 1491, 1303 (SO2), 1277, 1252, 1144
(SO2), 1111, 1073, 1023, 876, 828, 652. HRMS calcd. for
C24H23N2O6S (M+H+): 467.1277. found: 467.1275
J
2H), 3.79 (s, 3H), 2.39 (s, 3H).13C{H} NMR (125 MHz,
CDCl3) δ (ppm): 159.3, 149.0, 144.5, 142.7, 140.0, 138.0,
130.9, 129.8, 129.2, 128.8, 127.8, 116.2, 114.2, 114.1, 99.6,
55.2, 47.8, 21.5.IR νmax (KBr): 2923, 2853, 1514, 1304
(SO2), 1274, 1249, 1144 (SO2), 1082, 681, 645, 558. HRMS
calcd. for C22H21N2O3S (M+H+): 393.1275. found: 393.1256.
4.2.32
1-(4-methoxybenzyl)-3-(((4-methylthio)phenyl)
4.2.28.
1-(4-methoxybenzyl)-5-(4-methoxybenzyl)-3-((4-
sulfonyl)-5-(p-tolylethynyl)-1H-pyrrolo[2,3-b]pyridine (4ze)
methoxyphenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin (4za
)
1
Yield = 137 mg (51%); brown solid; mp = 184-185 °C; H
Yield = 120.7 mg (47%); light brown solid; mp = 165-166
NMR (500 MHz, CDCl3) δ (ppm): 8.59 (s, 1H), 8.37 (s, 1H),
1
°C; H NMR (500 MHz, CDCl3) δ(ppm): 8.63 (d,
J
= 2.1
7.89 (d,
J
= 8.2 Hz, 2H), 7.84 (s, 1H), 7.50 (d,
J
= 7.7 Hz,
= 7.7
Hz, 1H), 8.33 (d, = 2.1 Hz, 1H), 7.95-7.93 (m, 2H), 7.85
J
2H), 7.31-7.26 (m, 5H, one peak of CDCl3), 7.22 (d,
J
(s, 1H), 7.57-7.55 (m, 2H), 7.29-7.27 (m, 2H), 7.06-7.05 (m,
2H), 6.95-6.93 (m, 2H), 6.91-6.89 (m, 2H), 5.44 (s, 2H),
3.90 (s, 3H), 3.82 (s, 6H).13C{H} NMR (125 MHz, CDCl3)
δ(ppm): 162.9, 159.6, 159.4, 146.7, 144.1, 134.7, 132.2,
132.0, 131.0, 129.7, 128.8, 128.6, 127.6, 125.9, 116.8,
115.1, 114.5, 114.4, 114.3, 55.6, 55.4, 55.3, 48.3.IR νmax
(KBr): 3111, 2934, 2831, 1596, 1514, 1320, 1296 (SO2),
1257, 1178, 1141 (SO2), 831, 674, 596. HRMS calcd. for
C29H27N2O5S (M+H+): 515.1640. found : 515.1636.
Hz, 2H), 6.92-6.89 (m, 2H), 5.42 (s, 2H), 3.83 (s, 3H), 2.49
(s, 3H), 2.41 (s, 3H). 13C{H} NMR (125 MHz, CDCl3)
δ(ppm): 159.7, 147.8, 146.2, 146.0, 138.8, 138.5, 132.7,
131.5, 130.7 129.8, 129.2, 128.6, 127.2, 127.0, 125.5, 119.7,
116.3, 115.3, 114.8, 114.5, 113.9, 91.5, 86.0, 55.3, 48.4,
29.7 (acetone), 21.6, 14.7.IR νmax (KBr): 3110, 2922, 1513,
1390, 1310 (SO2), 1254, 1172, 1141 (SO2), 1089, 816, 755,
646, 615. HRMS calcd.for C31H27N2O3S2 (M+H+):
539.1463. found : 539.1448.
4.2.29.
1-(4-methoxybenzyl)-5-(4-methoxybenzyl)-3-(o-
4.2.33. (E)-1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-3-((4-
tolylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (4zb
)
methoxystyryl)sulfonyl)-1H-pyrrolo[2,3-b]pyridine (4zf
)
1
Yield = 87 mg (35%); white solid; mp = 127-128 °C; H
NMR (500 MHz, CDCl3) δ(ppm): 8.62 (d, = 2.0 Hz, 1H),
8.25 (d, = 7.8 Hz, 1H), 8.14 (d, = 1.9 Hz, 1H), 7.92 (s,
1H), 7.49 (d, = 8.6 Hz, 2H), 7.46-7.43 (m, 1H), 7.39 (t,
7.6 Hz, 1H), 7.29-7.28 (m, 3H, one peak of CDCl3),7.22 (d,
= 7.4 Hz, 1H), 7.03 (d, = 8.6 Hz, 2H), 6.91 (d, = 8.6
Hz, 2H), 5.49 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.54 (s,
3H). 13C{H} NMR (125 MHz, CDCl3) δ(ppm): 159.6, 159.4,
146.6, 144.2, 140.4, 137.5, 133.1, 133.1, 132.7, 132.0,
130.9, 129.6, 128.6, 128.4, 127.6, 126.5, 125.8, 117.0,
114.5, 114.4, 113.5, 55.4, 55.3, 48.3, 20.0.IR νmax (KBr):
3105, 2931, 2828, 1609, 1513, 1302 (SO2), 1240, 1178,
1162, 1147 (SO2), 1030, 827, 693, 605. HRMS calcd.for
C29H27N2O4S (M+H+): 499.1692. found : 499.1701.
Yield = 108 mg (40%); light yellow solid; mp = 142-143
1
J
°C; H NMR (500 MHz, CDCl3) δ (ppm): 8.56 (d,
Hz, 1H), 8.49 (d, = 4.1 Hz, 1H), 7.23 (d, = 8.4 Hz, 4H),
7.05 (d, = 15.3 Hz, 1H), 6.92 (d, = 8.5 Hz, 2H),6.86 (t,
= 7.6 Hz, 4H), 6.70 (d, = 8.5 Hz, 2H), 6.57 (d, = 15.3 Hz,
J = 7.8
J
J
J
J
J
J
=
J
J
J
J
J
J
J
J
1H), 5.34 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.74 (s,
3H).13C{H} NMR (125 MHz, CDCl3) δ(ppm): 161.6, 160.7,
158.9, 146.6, 144.7, 144.3, 140.2, 132.3, 130.0, 129.2,
129.0, 128.7, 125.8, 125.3, 120.3, 118.6, 118.0, 114.2,
113.7, 113.5, 112.0, 55.4, 55.3, 55.2, 45.6, 30.6 (acetone).IR
νmax (KBr): 3113, 3093, 2931, 2835, 1611, 1595, 1514, 1304
(SO2), 1246, 1174, 1141(SO2), 1115, 1033, 696, 620. HRMS
calcd. for C31H28ClN2O5S (M+H+): 541.1797. found :
541.1766.
4.2.30
benzyl)-5-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine
4zc
3-(benzo[d][1,3]dioxol-5-ylsulfonyl)-1-(4-methoxy
4.3. General procedure for deprotection of PMB group.
Compound 4j (82 mg, 0.2 mmol) was taken in a sealed tube
and kept it in ice. Added 2 ml TFA neat carefully dropwise
and stirred for 5 mins. Added 1.5 equiv. of mesitylene
(
)

13
5.
(a) Otzen T, Wempe EG, Kunz B, Bartels R, Lehwark-Yvetot G,
(36mg, 0.3 mmol), to the tube and stirred at 90° C for 5 h.
After the completion of reaction as indicated by TLC, the
reaction was quenched by the addition of sat. aq. NaHCO3
solution (10 mL) and diluted with CH2Cl2 (5 mL). The
aqueous layer was separated and extracted with CH2Cl2 (3 x
30 mL). The solvent was removed in vacuum and the crude
product was purified by silica flash column chromatography
Hansel W, Schaper K, Seydel JK, J. Med. Chem. 2004; 47:240-253. (b)
Harrak Y, Casula G, Basset J, Rosell G, Plescia S, Raffa D, Cusimano
MG, Pouplana R, Pujol MD, J. Med. Chem. 2010; 53:6560-6571. (c)
Xu W, Han F, He M, Hu D, He J, Yang S, Song B, J. Agric. Food
Chem. 2012; 60:1036-1041.
(a) Mileghem SV, De Borggraeve WMA, Org. Process Res. Dev.
2017; 21:785-787. (b) Qiu G, Zhoub K, Wu J, Chem. Commun. 2018;
54 :12561-12569; (c) Emmett EJ, Willis MC, Asian J. Org. Chem.
2015; 4:602-611.
(a) Woolven H, Gonzalez-Rodriguez C, Marco I, Thompson AL,
Willis MC, Org. Lett. 2011; 13:4876-4878. (b) Chen Y, Murray PRD,
Davies AT, Willis MC, J. Am. Chem. Soc. 2018; 140:8781-8787.
Rocke BM, Bahnck KB, Herr M, Lavergne S, Mascitti V, Perreault C,
Polivkova J, Shavnya A, Org. Lett. 2014; 16:154-157.
(a) Deeming AS, Russell CJ, Henessy AJ, Willis MC, Org. Lett. 2014;
16:150-153. (b) Lenstra DC, Vedovato V, Flegeau EF, Maydom J,
Willis MC, Org. Lett. 2016; 18:2086-2089.
6.
7.
to afford
3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(
Yield = 46mg (80%); white solid; mp = 234-235 °C; H
8 as white powder.
8
)
1
8.
9.
NMR (500 MHz, CDCl3) δ (ppm): 13.1 (s, 1H), 8.44 (d,
2.5 Hz, 1H), 8.23 (d, = 8.3 Hz, 1H), 8.02-8.00 (m, 1H),
= 8.3 Hz,
J =
J
7.64 -7.63 (m, 1H), 7.60-7.57 (m, 2H), 7.36 (d,
J
1H).13C{H} NMR (125 MHz, CDCl3) δ (ppm): 147.5, 145.6,
143.2, 133.6, 133.1, 130.9, 130.0, 126.8, 118.6, 115.2,
114.9. HRMS calcd. for C13H11N2O2S (M+H+): 293.0152.
found : 293.0178.
10. (a) Liu Y, Lin Q, Xiao Z, Zheng C, Guo Y, Chen Q, Liu C, Chem. Eur.
J. 2019; 25:1824-1828.
11. (a) Chen CC, Wase J, Org. Lett. 2015; 17:736-739. (b) Liu F, Wang J,
Zhou P, Li G, Hao W, Tu S, Jiang B, Angew. Chem. Int. Ed. 2017; 56
:15570-15574. (c) Shen Z, Wu Y, He C, He L, Hao W, Wang A, Tu S,
Jiang B, Chem. Commun. 2018; 54:445-448. (d) Wang A, Hao W, Zhu
Y, Li G, Zhou P, Tu S, Jiang B, ACS Omega 2018; 3:1482-1491. (e)
Liu S, Chen K, Hao W, Shu-Jiang Tu X–C, Jiang B, J. Org. Chem.
2019; 84:1964-1971.
12. (a) Tribby AL, Rodríguez I, Shariffudin S, Ball ND, J. Org. Chem.
2017; 82:2294-2299. (b) Vedovato V, Talbot EPA, Willis MC, Org.
Lett. 2018; 20:5493-5496.
Acknowledgments
This work was funded by UPOE-II, JNU and UGC-BSR mid-
career award sanctioned to VT. Urvashi thanks UGC- RGNFSC-
SRF for financial funding. We are thankful to AIRF, JNU and
USIC, Delhi University for providing Instrumentation facility.
13. Sun K, Shi Z, Liu Z, Luan B, Zhu J, Xue Y, Org. Lett. 2018; 20:6687-
6690.
Appendix A. Supplementary data
14. Zhu T, Zhang X, Zhao K, Loh T, Org. Chem. Front. 2019; 6:94-98.
15. (a) Tsai AS, Curto JM, Rocke BN, Dechert-Schmitt A-MR, Ingle GK,
Mascitti V, Org. Lett. 2016; 18:508-511. (b) Li G, Gan Z, Kong K,
Dou X, Yang D, Adv. Synth. Catal. 2019; 361:1808-1814.
16. (a) Wang H, Sun S, Chen J, Org. Lett. 2017; 19:5844-5847. (b) Wang
Y, Deng L, Deng Y, Han J, J. Org. Chem. 2018; 83:4674-4680. (c)
Zhang F, Zheng D, Lai L, Cheng J, Sun J, Wu J, Org. Lett. 2018;
20:1167-1170. (d) Willis MC, Phosphorus sulfur 2019; 194:654-657.
17. (a) Liu T, Zhou W, Wu J, Org. Lett. 2017; 19:6638-6641. (b) Yang D,
Sun P, Wei W, Liu F, Zhang H, Wang H, Chem. Eur. J. 2018;
24:4423-4427.
Supplementary data to this article can be found online at.
References and notes
1.
(a) Irie T, Sawa M, Chem. Pharm. Bull. 2018; 66:29-36. (b) Mérour
JY, Buron F, Plé K, Bonnet P, Routier S, Molecules 2014; 19:19935-
19979.
2.
For Vemurafenib see: (a) Mullard A, Nat. Rev. Drug Discov. 2012;
11:91-94. Recent selected papers: (b) Forster M, Chaikuad A, Dimitrov
T, Döring E, Holstein J, Berger B, Gehringer M, Ghoreschi K, Müller
S, Knapp S, Laufer SA, J. Med. Chem. 2018; 61:5350-5366. (c)
Adams ND, Adams JL, Burgess JL, Chaudhari AM, Copeland RA,
Donatelli CA, Drewry DH, Fisher KE, Hamajima T, Hardwicke MA,
J. Med. Chem. 2010; 53:3973-4001. (d) Butowski N, Colman H, De
Groot JF, Omuro AM, Nayak L, Wen PY, Cloughesy TF, Marimuthu
A, Haidar S, Perry A, Huse J, Phillips J, West BL, Nolop, Hsu HH,
Ligon KL, Molinaro KM, Prados M, Neuro Oncol. 2016; 18:557-564.
(e) Wang Y, Liu H, J. Med. Chem. 2018; 61:10412-10414. (f) Elsayed
MSA, Nielsen JJ, Park S, Park J, Liu Q, Kim CH, Pommier Y, Agama
K, Low PS, Cushman M, J. Med Chem. 2018; 61:10440-10462. (g)
Bernotasa RC, Lenicek S, Antane S, Cole DC, Harrison BL,
Robichaud AJ, Zhang GM, Smith D, Platt B, Qian Lin Q, Li P, Coupet
J, Rosenzweig-Lipsond S, Beyer CE, Schechter LE, Bioorg. Med.
Chem. 2009; 17:5153-5163.
18. Chen Y, Willis MC, Chem. Sci. 2017; 8:3249-3252.
19. (a) Urvashi; Tandon V, Das P, Kukreti S, RSC Adv. 2018; 8:34883-
34894. (b) Cardoza S, Das P, Tandon V, J. Org. Chem. 2019;
84:14015-14029.
20. (a) Lebrasseur N, Larrosa I, J. Am. Chem. Soc. 2008; 130:2926-2927.
(b) Jeanty M, Suzenet F, Delagrange P, Nosjean O, Guillaumet G,
Bioorg. Med. Chem. Lett. 2011; 21:2316-2319. (c) Kannaboina P,
Kumar KA, Aravinda S, Vishwakarma RA, Das P, Org. Lett. 2013;
15:5718-5721. (d) Tung Y, Coumar MS, Wu Y, Shiao H, Chang J,
Liou J, Shukla P, Chang C, Kuo C, Yeh T, Lin C, Wu J, Wu S, Liao C,
Hsieh H, J. Med. Chem. 2011; 54:3076-3080. (e) Iaroshenko VO,
Vilches-Herrera M, Gevorgyan A, Mkrtchyan S, Arakelyan K,
Ostrovskyi D, Abbasi MSA, Supe L, Hakobyan A, Villinger A,
Volochnyuk DM, Tolmachev A, Tetrahedron 2013; 69:1217-1228. (f)
Caldwell JJ, Cheung K, Collins I, Tetrahedron Lett. 2007; 48:1527-
1529.
21. (a) Dewanji A, Murarka S, Curran DP, Studer A, Org. Lett. 2013; 15
:6102-6105. (b) Goto A, Ohtsuki K, Ohfuji H, Tanishima M, Kaji H,
J. Am. Chem. Soc. 2013; 135:11131-11139.
22. Stallforth P, Adibekian A, Seeberger PH, Org, Lett. 2008; 10:1573-
1576.
3.
For the selected examples on azaindole and the references therein; (a)
Barl NM, Sansiaume‐Dagousset E, Karaghiosoff K, Knochel P,
Angew. Chem. Int. Ed. 2013; 52:10093-10096. (b) Li S, Wang C, Lin
H, Zhang X, Dong L, Org. Lett. 2015; 17:3018-3021. (c) Kannaboina
P, Kumar KA, Das P, Org. Lett. 2016; 18:900-903. (d) Kannaboina P,
Raina G, Kumar KA, Das P, Chem. Commun. 2017; 53:9446-9449. (e)
Dalziel ME, Patel JJ, Kaye M, Cosman KJL, Kitching MO, Snieckus
V, Angew. Chem. Int. Ed. 2019; 58:7313-7395. (f) Pires MLD, Poeira
DL, Purificação SL, Marques MMB, Org. Lett. 2016; 18:3250-3253.
(g) Plas A, Martin C, Joubert N, Viaud-Massuard M-C, Org Lett. 2015;
17:4710-4713. (h) Mishra A, Vats TK, Nair MP, Das A, Deb I, J. Org.
Chem. 2017; 82:12406-12415. (i) Jeon T, Lee SH, Chun R, Han S, Han
SH, Jeon YU, Park J, Yoshimitsu T, Mishra NK, Kim IS, J. Org.
Chem. 2018; 83:4641-4649. (j) Pan C, Wang Y, Wu C, Yu JT, Org.
Biomol. Chem. 2018; 16:3711-3715.
23. (a) Haddleton DM, Jasieczek CB, Hannon MJ, Shooter AJ,
Macromolecules 1997; 30:2190-2193. (b) Gamez P, Arends IWCE,
Sheldon RA, Reedijk J, Adv. Synth. Catal. 2004; 346:805-811.
24. Qiu G, Lai L,Cheng J, Wu J, Chem. Commun. 2008; 54:10405-10414.
4.
For coupling reactions and references therein: (a) Molnar A, Chem.
Rev. 2011; 111:2251-2320. (b) Bariwal J, Eycken EV, Chem. Soc. Rev.
2013; 42:9283-9303. (c) Bruno NC, Tudge MT, Buchwald SL, Chem.
Sci. 2013; 4:916-920. (d) Lee C, Liu Y, Badsara SS, Chem. Asian J.
2014; 9:706-722. (e) Ruiz-Castillo P, Buchwald SL, Chem. Rev. 2016;
116:12564-12649.

Declaration of interests
V The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: