Ruthenium-Catalyzed Direct and Selective C-H Cyanation of N-(Hetero)aryl-7-azaindoles

Article abstract of DOI:10.1021/acs.joc.6b01148

An efficient, highly regioselective, and scalable ruthenium-catalyzed o-aryl C-H mono-cyanation of N-aryl-7-azaindoles to form N-(2-cyanoaryl)-7-azaindoles has been developed through N-directed ortho C-H activation using N-cyano-N-phenyl-p-toluenesulfonam

Full text of DOI:10.1021/acs.joc.6b01148

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Article
Ruthenium-Catalyzed Direct and Selective C–
H Cyanation of N-(Hetero)aryl-7-azaindoles
Aniket Mishra, Tripta Kumari Vats, and Indubhusan Deb
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01148 • Publication Date (Web): 13 Jul 2016
Downloaded from http://pubs.acs.org on July 15, 2016
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Ruthenium-Catalyzed Direct and Selective C–H Cyanation of N-(Hetero)aryl-7-azaindoles
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Aniket Mishra, Tripta Kumari Vats and Indubhusan Deb *
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Organic and Medicinal Chemistry Division, Indian Institute of Chemical Biology, 4-Raja S. C.
Mullick Road, Jadavpur, Kolkata 700032, India.
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Eꢀmail: indubhusandeb@iicb.res.in
Abstract: An efficient, highly regioselective and scalable rutheniumꢀcatalyzed ortho aryl C–H
mono cyanation of Nꢀarylꢀ7ꢀazaindoles to form Nꢀ(2ꢀcyanoaryl)ꢀ7ꢀazaindoles has been
developed through N-directed ortho C–H activation using NꢀcyanoꢀNꢀphenylꢀpꢀtoluene
sulfonamide as cyanating reagent in presence of AgOTf and NaOAc in DCE. A range of
substrates has furnished cyanated azaindoles in good to excellent yields under the simple
reaction conditions. Involvement of C–H metalation has been supported by kinetic study. This
methodology provides an easy access to a class of pharmaceutically significant molecules and
their precursors.
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INTRODUCTION
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Azaindole is a unique heterocyclic moiety present in various biologically active
molecules,1 novel synthetic materials,2 and has been found in various marketed drugs3
including vemurafenib. On the other hand, the nitrile group is of great research interest in
the area of organic and medicinal chemistry and plays an important role in organic
synthesis due to its easy conversion into many other important functional groups like
amine, aldehyde, amide, ester and various heterocyclic scaffolds.4 A large number of
bioactive natural products and drug molecules such as letrozole, fadrozole and citalopram
also feature cyano group(s) (Figure 1).5
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Figure 1. Bioactive molecules
NC
CN
NHSO2Ph
CN
N
N
N
N
N
N
N
N
N
N
N
F
N
N
H
Letrozole
Antineoplastic
GABA receptor antagonist
PI3K/m TOR inhibitor
Over the past decades, direct C–H/C–X functionalization has been considered as a
practical alternate catalytic approach to conventional cyanation reactions such as
Rosenmundꢀvon Braun6 reaction and diazotization followed by Sandmeyer reaction,7
which uses an excess amount of hazardous cyanating reagents. In this context, various
methods employing transition metal catalysis have been developed.8 Several organoꢀ
cyanating reagent including cyanohydrin, DMFꢀNH3, PhTsNCN, MeCN and MeNO2
have been reported for cyanation reaction.9 During the last few years, transition metals,
mainly rhodium and cobalt catalyzed chelating groups such as oxime,10 pyridine,11
pyrimidine,12 amide,13 azo,14 nitrileoxide15 and phosphonate16 ꢀassisted catalytic C–H
activation has emerged as a powerful approach for C–H cyanation using NCTS. Though
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ruthenium catalysis17 is well known for C–H bond functionalization, directing group
assisted C–H cyanation employing ruthenium remains less explored.13a In spite of the
known importance of the azaindole scaffold in medicinal chemistry and in material
chemistry, only a limited number of metal catalyzed functional group incorporations have
been achieved. For example, palladiumꢀcatalyzed amination, C2ꢀC3 arylation, C3ꢀ
alkenylation and selective C6 arylation of azaindoles have been reported.18
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Recently, 7ꢀazaindole directed catalytic C–H chlorination using DCE as a chloride
source, oxidative annulation with alkyne, C–C coupling with vinyl acetate and
alkynylation have been reported using expensive rhodium or iridium catalysts (Scheme 1,
eq 1).19 However, to date, azaindole directed catalytic and selective C–H cyanation using
transition metals has not been reported. Thus, a catalytic approach for the direct and
selective C–H cyanation of azaindole appeared highly desirable. In continuation of our
research interest in metal catalyzed C–H bond functionalization,20 herein we wish to
reveal Nꢀdirected selective C–H cyanation reaction of
relatively less expensive [RuCl2( ꢀcymene)]2 catalyst and the easily accessible,
ꢀphenylꢀ ꢀtoluene sulfonamide (NCTS) , as the cyanating reagent in presence of
Nꢀarylꢀ7ꢀazaindole using the
p
Nꢀcyanoꢀ
N
p
2
additives AgOTf and NaOAc in DCE (Scheme 1, eq 2).
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Scheme 1. 7ꢀazaindole directed C–H bond functionalization
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RESULTS AND DISCUSSION
We initiated our study by performing cyanation reaction of arenes using Nꢀphenylꢀ7ꢀ
azaindole 1a as a substrate under different conditions. To our delight, screening of different
nitrile sources such as benzyl cyanide, isocyanide and Nꢀcyano succinimide (see SI, table S1)
revealed NCTS to be an efficient cyanating reagent to provide ortho cyanated Nꢀphenylꢀ7ꢀ
azaindole 3a in 84% yield at 110 °C (Table 1, entry 1) in presence of [RuCl2(pꢀcymene)]2 (5
mol%) as catalyst and AgOTf (30 mol%) and NaOAc (50 mol%) as coꢀcatalysts in DCE without
the formation of any C2 or C3 cyanation product. The use of other catalytic conditions for
cyanation did not give satisfactory results (see SI, table S1). No cyanation reaction occurred in
absence of catalysts and silver salt (Table 1, entries 14 and 15). Screening of different solvents
(chlorobenzene, toluene and 1,4ꢀdioxane) other than DCE resulted in poor yield of the cyanated
product (Table 1, entries 4 and 5). On the other hand, replacement of NaOAc with other
additives (CsOAc, Cu(OAc)2 and AgOAc) (see SI, table 1) proved less effective or not effective
at all. Decreasing the amount of AgOTf (10 mol%) and NaOAc (30 mol%) did not improve the
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yield, while increasing the proportion of NaOAc (100 mol%) also furnished less product ( Table
1, entries 8, 10 and 11).
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Table 1. Optimization of condition for cyanation of Nꢀarylꢀ7ꢀazaindolesa
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Ph
(2 equiv)
N
Ts
CN
2
N
[RuCl2(p-cymene)]2 (5 mol%)
N
H
N
N
CN
AgOTf (30 mol%)
NaOAc (50 mol%)
DCE (0.1 M), 110 oC, 30 h
1a
3a
entry deviation from standard condition
Yield (%)b
of 3a
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2
None
84
RuCl3 (10 mol%) instead of [RuCl2(pꢀ nr
cymene)]2
3
[Cp(pꢀcymene)Ru (II)]PF6 (5 mol%) instead of nr
[RuCl2(pꢀcymene)]2 (5 mol%)
4
Toluene or 1,4ꢀdioxane instead of DCE
Chlorobenzene instead of DCE
3 mol% of [RuCl2(pꢀcymene)]2
50 mol% of AgOTf
trace
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32
67
63
64
82
78
68
52
61
nr
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10 mol% of AgOTf
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AgSbF6 instead of AgOTf
30 mol% of NaOAc
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100 mol% of NaOAc
80 oC
Omitting NaOAc
Omitting AgOTf
Omitting [RuCl2(p cymene)]2/AgOTf/NaOAc
nr
a
Reaction conditions: unless otherwise mentioned all reactions were performed with a mixture
of 1a (0.2 mmol), 2 (2 equiv), [RuCl2(pꢀcymene)]2 (5 mol%), AgOTf (30 mol%) and NaOAc (50
mol%) in DCE (0.1 M) at 110 °C, under N2 for 30 h. b Isolated yield. nr: no reaction.
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Lowering the catalyst loading (Ru(II), 3 mol%) furnished the product to the extent
of 67% only (Table 1, entry 6). Although use of AgSbF6 (30 mol%) gave the product in
82% yield (Table 1, entry 9), the relatively less hygroscopic AgOTf (30 mol%) was
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considered more economical. Decrease in the reaction temperature to 80 °C lowered the
yield (Table 1, entry 12). Although, the reaction proceeds well in absence of NaOAc
(Table 1, entry 13) which is common in ruthenium catalysis,17 the presence of NaOAc is
essential to obtain the cyanated product in excellent yield, it might be due the formation
of relatively more active carboxylate complex of ruthenium.
Employing the optimized catalytic conditions, array of
Nꢀarylꢀ7ꢀazaindoles were
subjected to cyanation to evaluate the scope of the reaction (Scheme 2). The results
showed that various substituents at different positions were tolerated and no bisꢀcyanated
product resulted. Electronꢀdonating groups on arenes undergoing C–H functionalization
are generally favourable for this cyanation reaction, except for the 2ꢀsubstituted aryl
substrate 3g. Gratifyingly, meta substituted substrates 1bꢀ1e yielded the cyanated
products 3b-3d in excellent yields and excellent regioselectivity, the less sterically
hindered site of the substrates being favoured for functionalization. In case of para
substituted substrates the desired cyanated products 3jꢀ3p were obtained in better yields
when the group was electronꢀdonating (except 3n). Pleasingly, heteroarenes 1r-1t were
also efficiently cyanated using the optimized catalytic system and provided the
corresponding cyanated benzothiophene 3r, thiophene 3s, and furans 3t in good yields,
except 3u which was obtained in moderate yield.
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Scheme 2. Scope of cyanation of Nꢀarylꢀ7ꢀazaindolesa
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Ph
N
(2 equiv)
Ts
CN
2
N
[RuCl2(p-cymene)]2 (5 mol%)
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N
H
N
N
CN
AgOTf (30 mol%)
NaOAc (50 mol%)
DCE (0.1 M), 110 oC, 30 h
R
R
1
3
N
N
N
N
N
N
CN
OMe
N
N
CN
CN
CN
MeO
3e, 75%
Me2N
Me
MeO
3b, 81%
3c, 83%
3d, 80%
3f, R = OMe, 87%
3g, R = Me, 41%
3j, R = OMe, 60%
3k, R = Me, 66%
3l, R = tBu, 80%
N
N
N
CN
N
3h, R = COMe, 51%
3i, R = CO2Me, 66%
CN
R
3m, R = Ph, 75%
3n, R = NMe2, 34%
3o, R = CO2Me, 51%
3p, R = COMe, 44%
3f-3i
N
N
R
CN
3j-3p
3q, 78%
N
N
N
N
N
N
CN
CN
CN
S
N
N
O
CN
O
S
3r, 78%
3t, 64%
3u, 39%
3s, 87%
a
Reaction condition: Mixture of 1 (0.2 mmol), 2 (2 equiv), [RuCl2(pꢀcymene)]2 (5 mol%),
AgOTf (30 mol%) and NaOAc (50 mol%) in DCE (0.1 M) at 110 °C, under N2 for 30 h. Yields
refer to isolated products.
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In general, substrates bearing electronꢀwithdrawing groups provided the cyanation
products in moderate yields. Singleꢀcrystal Xꢀray study of 3q confirmed the structure of
the cyanated product (SI).
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Next, we turned our attention to substituted 7ꢀazaindoles. Using the optimized
conditions, substrates 1v-1af were successfully converted to cyanated products 3v-3af in
good to excellent yields (Scheme 3). Substrates possessing aryl groups reacted smoothly
to afford the products 3v-3aa and 3ad in good yields. It should be noted that a halide such
as iodo or bromo at 3 position of 7ꢀazaindole ring exerted only a minor effect on the
yields of 3ab and 3ac. This finding encouraged us to extend this methodology and
explore whether
Nꢀarylꢀαꢀcarbolines 1ae-1af could also be cyanated. Substrates 1ae-1af
indeed participated in the reaction and afforded the desired cyanated
Nꢀarylꢀαꢀcarboline
products 3ae-3af in 72% and 81% yields, respectively (Scheme 3).
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Scheme 3. Scope of cyanation of Nꢀarylꢀ7ꢀazaindolesa
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4
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7
8
9
Ph
N
(2 equiv)
Ts
CN
R'
2
R'
N
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N
[RuCl2(p-cymene)]2 (5 mol%)
N
H
CN
N
AgOTf (30 mol%)
NaOAc (50 mol%)
DCE (0.1 M), 110 oC, 30 h
R
R
3
1
Ar
Ph
N
Ar
Ph
N
N
N
CN
N
N
N
N
CN
CN
CN
3y, Ar = (4-Br-C6H4), 88%
3z, Ar = (4-F-C6H4), , 75%
3w, 75%,
Ar = (3-Me-C6H4)
3x, 74%
3v, 50%,
I
Br
N
CN
N
N
N
N
CN
N
CN
3aa, 51% b
3ab, 67%
3ac, 83%
Ar
N
N
N
N
N
CN
CN
N
CN
3ad, 66%
Me
Ar = (4-Cl-C6H4),
3ae, 72%
3af, 81%
a
Reaction condition: mixture of 1 (0.2 mmol), 2 (2 equiv), [RuCl2(pꢀcymene)]2 (5 mol%),
AgOTf (30 mol%) and NaOAc (50 mol%) in DCE (0.1 M) at 110 °C, under N2 for 30 h. Yields
refer to isolated products.
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To illustrate the scalability of the cyanation, we conducted a gram scale experiment using
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the substrate 1a (1 g) and obtained the cyanated product 3a (0.79 g) in 70% yield. The
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nitrile bearing
provide amine
N
ꢀarylꢀ7ꢀazaindole 3a underwent smooth synthetic transformations to
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4
and amide in good yields (Scheme 4), underlining the utility of the
5
cyanide product as synthetic intermediate.
Scheme 4. Synthetic transformations of cyanated Nꢀphenylꢀ7ꢀazaindole
To prove the possible mechanism of the cyanation reaction, several experiments
were conducted (Scheme 5). Rapid ortho H–D exchange of 1a in presence of excess
amount of D2O clearly suggested that reversible cleavage of C–H bond may be involved
in the C–H cyanation. Low kinetic isotope effect (KIE) values of 1.6 and 1.2 were found
in both parallel and competitive experiment between 1a and 1a-d5, implying that the
cleavage of the ortho C–H bond may not be the rate–limiting step in the mechanism. No
significant substituent effect was observed in competitive experiment of the substrate 1a
and 1f
.
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Scheme 5. Mechanistic experiments
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7
H/D exchange experiment
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[RuCl2(p-cymene)]2 (5 mol%)
'
N
N
AgOTf (30 mol%)
N
N
H/D
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H
H/D
H
NaOAc (50 mol%)
DCE (0.1 M), 110 oC, 30 h
D2O (20 equiv)
1a-dn, 82% (75% D)
1a
Parallel experiment between1a and 1a-d5
(2 equiv)
2
[RuCl2(p-cymene)]2 (5 mol%)
N
AgOTf (30 mol%)
N
N
N
N
D
N
CN
H
or
NaOAc (50 mol%)
D4
DCE (0.1 M), 110 oC, 0.5-2.5 h
kH/kD = 1.6
D4/H4
H4
1a-d5
3a or 3a-d4,
1a
Competitive experiment between1a and 1a-d5
(2 equiv)
2
[RuCl2(p-cymene)]2 (5 mol%)
N
AgOTf (30 mol%)
N
N
N
N
D
N
CN
H
+
NaOAc (50 mol%)
D4
DCE (0.1 M), 110 oC, 2 h
D4/H4
3a + 3a-d4,
H4
1a-d5
1a
kH/kD = 1.2
Competitive experiment between1a and 1f
(2 equiv)
2
[RuCl2(p-cymene)]2 (5 mol%)
N
N
N
AgOTf (30 mol%)
N
N
N
CN
CN
H
+
H
MeO
H/OMe
NaOAc (50 mol%)
DCE (0.1 M), 110 oC, 30 h
3a, 49%
3f 30%
1a/1f
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Based on the mechanistic studies as shown in scheme 5 and previous report,13a it appears
that the reaction is involved in the formation of monomeric active cationic ruthenium
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7
8
9
complex
reversible C–H ruthenation of
6). Coꢀordination of NCTS 2 with
insertion leads the formation of . The intermediate
afford the desired cyanated product and the intermediate
is regenerated to continue the redox neutral catalytic cycle by elimination of
tosylaniline from via protoꢀdemetalation.
A
from [RuCl2(
p
ꢀcymene)]2 in presence of AgOTf and NaOAc followed by
ꢀarylꢀ7ꢀazaindole 1a produces ruthenacycle (Scheme
forms the intermediate , which upon migratory
undergoes βꢀamine elimination to
. The active catalytic species
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N
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Scheme 6. Plausible reaction mechanism
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CONCLUSIONS
In summary, we have demonstrated a direct and selective C–H cyanation of
arylꢀ7ꢀazaindoles with a broad range of substrate scope using the relatively less expensive
[RuCl2(pꢀcymene)]2 catalyst and the easily accessible, ꢀcyanoꢀ ꢀphenylꢀ ꢀtoluene
sulfonamide (NCTS) , as an electrophilic cyanating reagent in presence of additives
Nꢀ
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N
N
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AgOTf and NaOAc in DCE solvent.
EXPERIMENTAL SECTION
General Information:
All reactions were carried out in oven dry reaction vessel under nitrogen atmosphere
unless otherwise mentioned. TLC analysis was performed on Merck 60 F254 silica gel TLC
plates. Column chromatography was done using 230ꢀ400 mesh silica gel or neutral alumina
(activity IꢀII) applying pressure through air pump. 1H and 13CNMR spectra were recorded on 300
and 600 MHz spectrometer and are reported as chemical shifts (δ) in parts per million (ppm) and
multiplicities are abbreviated as s = singlet, d = doublet, t = triplet, m = multiplet, comp =
complex. Internal standards or residual solvent signals were used as reference. HRMS (m/z) was
recorded in QꢀTof Micro mass spectrometer (LCꢀMS, ESI mode) and EI mode. Melting points
were determined in a capillary melting point apparatus and are uncorrected. GC analysis was
done in a GC system with Flame Ionizing Detector (FID). Single crystal Xꢀray data was recorded
in a diffractometer with MoKα radiation. The CIF is submitted into CCDC (1472438) and can be
obtained through https://summary.ccdc.cam.ac.uk/structureꢀsummaryꢀform.
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Preparation of starting materials:
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All 7ꢀazaindoles are commercially available. Nꢀarylꢀ7ꢀazaindoles were prepared by Nꢀ
arylation of 7ꢀazaindoles using appropriate aryl iodides (1a,1b, 1d,1f, 1g, 1h, 1i, 1j, 1k, 1l, 1o,
1p, 1q, 1s, 1ab, 1ae and 1af)19a, 21 or aryl bromides (d5ꢀ1a,1c, 1e, 1n, 1r, 1t and 1u)22 following
literature procedure. 1ac was prepared by iodination of 1a with NIS.19a Nꢀaryl 7ꢀazaindoles (1m,
1v, 1w, 1x, 1y, 1z, 1aa and 1ad) were prepared using appropriate bromo Nꢀarylꢀ7ꢀazaindoles and
appropriate boronic acids following Suzuki cross coupling method.19a Characterization data of
newly synthesized Nꢀarylꢀ7ꢀazaindoles are given below. All the reported (1a19a, 1b19a, 1d19a,
1j19a, 1k19a, 1m19a, 1o19a, 1p19a, 1s23, 1v19a, 1x19a, 1ab19a, 1ac19a, 1ad19a, 1ae24 and 1af24) Nꢀarylꢀ7ꢀ
azaindoles are in good agreement with literature data.
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NꢀcyanoꢀNꢀphenylꢀpꢀtoluenesulfonamide (NCTS) was prepared following literature
procedure and is in good agreement with literature data.10
Characterization data of Starting Materials:
N,N-dimethyl-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)aniline (1c): Yield: 71%; colourless
ο
1
solid; mp: 78 – 79 C; H NMR: (300 MHz, CDCl3) δ 3.03 (s, 6 H), 6.62 (d, J = 3.6 Hz, 1 H),
6.73 (dd, J = 8.1 Hz, 2.6 Hz, 1 H), 7.03 – 7.10 (comp, 2 H), 7.14 (dd, J = 7.8 Hz, 4.6 Hz, 1 H),
7.38 (t, J = 7.2 Hz, 1 H), 7.54 (d, J = 3.6 Hz, 1 H), 7.98 (dd, J = 7.8 Hz, 1.8 Hz, 1 H), 8.39 (dd, J
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= 4.8 Hz, 1.8 Hz, 1 H); C NMR: (75 MHz, CDCl3) δ 40.5, 100.9, 108.4, 110.6, 112.2, 116.3,
121.3, 128.2, 128.8, 129.7, 139.2, 143.4, 147.5, 151.2; HRMS: (EI, m/z) calcd for C15H15N3 [M]+
237.1266, observed 237.1253.
1-(3,5-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (1e): Yield: 11%; colourless solid;
mp: 54 – 55 οC; 1H NMR: (600 MHz, CDCl3) δ 3.88 (s, 6 H), 6.47 (t, J = 2.4 Hz, 1 H), 6.64 (d, J
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= 3.6 Hz, 1 H), 6.99 (d, J = 1.8 Hz, 1 H), 7.16 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.53 (d, J = 4.2 Hz,
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1 H), 7.99 (dd, J = 7.2 Hz, 1.8 Hz, 1 H), 8.40 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); C NMR: (150
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MHz, CDCl3) δ 55.5, 98.4, 101.6, 102.6, 116.6, 121.6, 127.9, 129.0, 140.0, 143.6, 147.5, 161.1;
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HRMS: (EI, m/z) calcd for C15H14N2O2 [M]+ 254.1055, observed 254.1049.
1-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (1f): Yield 67%; pale brown solid; mp:
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87 – 88 C; H NMR: (300 MHz, CDCl3) δ 3.79 (s, 3 H), 6.61 (d, J = 3.6 Ηz, 1 H), 7.08 – 7.15
(comp, 3 H), 7.37 – 7.43 (comp, 2 H), 7.56 (dd, J = 7.5 Ηz, 1.8 Ηz, 1 H), 7.97 (dd, J = 7.8 Ηz,
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1.5 Ηz, 1 H), 8.33 (dd, J = 4.8 Ηz, 1.5 Ηz, 1 H); C NMR: (150 MHz, CDCl3) δ 55.8, 100.3,
112.4, 116.2, 120.6, 120.9, 126.7, 128.7, 128.7, 128.8, 130.1, 143.4, 148.2, 154.4; HRMS: (EI,
m/z) calcd for C14H12N2O [M]+ 224.0950, observed 224.0940.
1-(o-tolyl)-1H-pyrrolo[2,3-b]pyridine (1g): Yield: 27%; yellow oil; 1H NMR: (300 MHz,
CDCl3) δ 2.11 (s, 3 H), 6.64 (d, J = 3.6 Ηz, 1 H), 7.12 (dd, J = 7.5 Ηz, 4.8 Ηz, 1 H), 7.29 (d,
J = 3.3 Ηz, 1 H), 7.34 – 7.41 (comp, 4 H), 8.00 (dd, J = 7.8 Ηz, 1.5 Ηz, 1 H), 8.35 (dd,
J = 4.8 Ηz, 1.5 Ηz, 1 H); 13C NMR: (75 MHz, CDCl3) δ 17.9, 100.6, 116.0, 120.4, 126.6, 128.1,
128.4, 128.8, 129.1, 131.1, 135.8, 137.1, 143.6, 148.0; HRMS: (ESI, m/z) calcd for C14H12N2Na
[M+Na]+ 231.0898, observed 231.0893.
1-(2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)ethanone (1h): Yield: 67%; yellow solid;
mp: 57 – 59 οC; 1H NMR: (300 MHz, CDCl3) δ 1.97 (s, 3 H), 6.68 (d, J = 3.6 Ηz, 1 H), 7.13 (dd,
J = 7.8 Ηz, 4.8 Ηz, 1 H), 7.34 (d, J = 3.6 Ηz, 1 H), 7.46 – 7.52 (comp, 2 H), 7.64 (td, J = 7.8 Ηz,
4.8 Ηz, 1 H), 7.76 (dd, J = 7.5 Ηz, 2.1 Ηz, 1 H), 7.98 (dd, J = 8.1 Ηz, 1.8 Ηz, 1 H), 8.31 (dd,
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J = 4.5 Ηz, 1.8 Ηz, 1 H); C NMR: (75 MHz, CDCl3) δ 28.4, 102.2, 116.9, 120.9, 127.9, 128.0,
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128.8, 129.1, 129.3, 132.3, 135.7, 137.5, 143.9, 148.0, 200.7; HRMS: (EI, m/z) calcd for
C15H12N2O [M]+ 236.0950, observed 236.0945.
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methyl 2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate (1i): Yield: 57%; brown solid; mp: 60
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– 63 C; H NMR: (300 MHz, CDCl3) δ 3.46 (s, 3 H), 6.65 (d, J = 3.6 Ηz, 1 H), 7.10 (dd,
J = 7.8 Ηz, 4.8 Ηz, 1 H), 7.38 (d, J = 3.6 Ηz, 1 H), 7.47 – 7.52 (comp, 2 H), 7.68 (td, J = 7.8 Ηz,
1.5 Ηz), 7.97 (dd, J = 7.8 Ηz, 1.5 Ηz), 8.03 (dd, J = 7.8 Ηz, 1.5 Ηz), 8.29 (dd, J = 4.8 Ηz,
1.5 Ηz); 13C NMR:(75 MHz, CDCl3) δ 52.0, 101.4, 116.4, 120.8, 127.5, 128.0, 128.6, 128.8,
129.0, 131.2, 132.8, 137.2, 143.4, 148.3, 166.7; HRMS: (EI, m/z) calcd for C15H12N2O2 [M]+
252.0899, observed 252.0902.
1-(4-(tert-butyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (1l): Yield: 98%; colourless solid;
mp: 89 – 90 οC; 1H NMR: (300 MHz, CDCl3) δ 1.37 (s, 9 Η), 6.62 (d, J = 3.6 Ηz, 1 H), 7.12 (dd,
J = 7.8 Ηz, 4.8 Ηz, 1 H), 7.50 (d, J = 3.6 Ηz, 1 H), 7.52 – 7.57 (comp, 2 H), 7.63 – 7.67 (comp, 2
13
H), 7.98 (dd, J = 7.8 Ηz, 1.5 Ηz, 1 H), 8.38 (dd, J = 4.5 Ηz, 1.8 Ηz, 1 H); C NMR:(75 MHz,
CDCl3) δ 31.3, 34.5, 101.2, 116.4, 121.3, 123.6, 126.2, 127.9, 128.9, 135.7, 143.4, 147.4,
149.1; HRMS: (EI, m/z) calcd for C17H18N2 [M]+ 250.1470, observed 250.1476.
N,N-dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)aniline (1n): Yield: 88%; brown solid;
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mp: 92 – 93 C; H NMR: (300 MHz, CDCl3) δ 3.02 (s, 6 H), 6.60 (d, J = 3.3 Ηz, 1 H), 6.85 –
6.90 (comp, 2 H), 7.11 (dd, J = 7.8 Ηz, 4.5 Ηz, 1 H), 7.45 (d, J = 3.6 Ηz, 1 H), 7.51 – 7.56
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(comp, 2 H), 7.98 (dd, J = 8.1 Ηz, 1.8 Ηz, 1 H), 8.37 (dd, J = 4.5 Ηz, 1.8 Ηz, 1 H); C NMR:
(75 MHz, CDCl3) δ 40.7, 100.3, 113.0, 116.0, 121.0, 125.4, 127.8, 128.5, 128.7, 143.3, 147.6,
149.3; HRMS: (EI, m/z) calcd for C15H15N3 [M]+ 237.1266, observed 237.1264.
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1-(naphthalen-1-yl)-1H-pyrrolo[2,3-b]pyridine (1q): Yield: 83%; colourless solid; mp:
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98 – 99 C; H NMR: (300 MHz, CDCl3) δ 6.73 (d, J = 3.3 Hz, 1 H), 7.15 (dd, J = 7.8 Hz, 4.5
Hz, 1 H), 7.38 – 7.42 (comp, 2 H), 7.46 (d, J = 3.6 Hz, 1 H), 7.50 – 7.56 (m, 1 H), 7.61 – 7.64
(comp, 2 H), 7.59 – 7.66 (comp, 2 H), 8.06 (dd, J = 7.8 Hz, 1.5 Hz, 1 H), 8.31 (dd, J = 4.8 Hz,
1.8 Hz, 1 H); 13C NMR: (75 MHz, CDCl3) δ 100.9, 116.4, 120.5, 123.1, 125.4, 125.6, 126.4,
126.8, 128.2, 128.8, 129.0, 130.3, 130.7, 134.4, 134.7, 143.8, 149.0; HRMS: (ESI, m/z) calcd for
C17H12N2Na [M+Na]+ 267.0898, observed 267.0892.
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1-(benzo[b]thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridine (1r): Yield: 84%; yellow solid;
mp: 66 – 67 C; 1H NMR: (300 MHz, CDCl3) δ 6.70 (d, J = 3.6 Hz, 1 H), 7.16 (dd, J = 7.8 Hz,
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4.8 Hz, 1 H), 7.34 – 7.45 (comp, 2 H), 7.52 (d, J = 3.6 Hz, 1 H), 7.60 (dd, J = 7.2 Hz, 2.1 Hz, 1
H), 7.67 (s, 1 H), 7.92 (dd, J = 7.2 Hz, 1.2 Hz, 1 H), 8.02 (dd, J = 7.8 Hz, 1.8 Hz, 1 H), 8.36 (dd,
J = 4.8 Hz, 1.5 Hz, 1 H); 13C NMR: (75 MHz, CDCl3) δ 101.4, 116.8, 120.8, 121.2, 121.9, 123.1,
124.6, 125.1, 129.0, 129.1, 130.8, 134.9, 138.8, 143.8, 148.2; HRMS: (EI, m/z) calcd for
C15H10N2S [M]+ 250.0565, observed 250.0573.
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1-(furan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1t): Yield: 97%; brown oil; H NMR: (300
MHz, CDCl3) δ 6.57 (dd, J = 3.0 Hz, 2.1 Hz, 1 H), 6.62 (d, J = 3.6 Hz, 1 H), 6.72 (dd, J = 3.6
Hz, 0.9 Hz, 1 H), 7.16 (dd, J = 7.8 Hz, 4.5 Hz, 1 H), 7.33 (dd, J = 2.1 Hz, 1.2 Hz), 7.61 (d, J =
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3.6 Hz, 1 H), 7.96 (dd, J = 7.8 Hz, 1.5 Hz, 1 H), 8.42 (dd, J = 4.5 Hz, 1.8 Hz, 1 H); C NMR:
(75 MHz, CDCl3) δ 97.0, 102.3, 111.6, 117.0, 121.1, 125.8, 129.0, 137.4, 143.9, 144.9, 146.6;
HRMS: (ESI, m/z) calcd for C11H8N2ONa [M+Na]+ 207.0534, observed 207.0527.
1-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridine (1u): Yield: 98%; brown solid; mp: 61 – 62 οC;
1H NMR: (300 MHz, CDCl3) δ 6.59 (d, J = 3.6 Hz, 1 H), 6.87 (dd, J = 1.8 Hz, 0.6 Hz, 1 H), 7.12
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(dd, J = 7.8 Hz, 4.5 Hz, 1 H), 7.41 (d, J = 3.6 Hz, 1 H), 7.48 (t, J = 1.8 Hz, 1 H), 7.93 (dd, J = 7.8
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Hz, 4.5 Hz, 1 H), 8.27 (dd, J = 1.2 Hz, 0.9 Hz, 1 H), 8.40 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); C
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NMR: (75 MHz, CDCl3) δ 101.6, 105.6, 116.5, 121.2, 125.8, 126.5, 128.9, 133.2, 142.4, 143.6,
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147.0; HRMS: (EI, m/z) calcd for C11H8N2O [M]+ 184.0637, observed 184.0624.
1-phenyl-4-(m-tolyl)-1H-pyrrolo[2,3-b]pyridine (1w): Yield: 98%; colourless solid; mp:
143 – 145οC; 1H NMR: (300 MHz, CDCl3) δ 2.49 (s, 3 H), 6.84 (d, J = 3.6 Hz, 1 H), 7.22 (app d,
J = 4.8 Hz, 1 H), 7.29 (app d, J = 7.5 Hz, 1 H), 7.37 (app t, J = 7.2 Hz, 1 H), 7.44 (app t, J = 7.8
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Hz, 1 H), 7.53 – 7.59 (comp, 5 H), 7.77 – 7.80 (comp, 2 H), 8.43 (app d, J = 5.1 Hz, 1 H); C
NMR: (75 MHz, CDCl3) δ 21.6, 101.2, 116.0, 119.6, 124.2, 125.8, 126.4, 128.1, 128.8, 129.2,
129.3, 129.4, 138.6 (2 C), 138.7, 142.6, 143.9, 148.1; HRMS: (EI, m/z) calcd for C20H16N2 [M]+
284.1313, observed 284.1317.
5-(4-bromophenyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine (1y): Yield: 29%; colorless
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solid; mp: 172 – 173 C; H NMR: (300 MHz, CDCl3) δ 6.71 (d, J = 3.6 Hz, 1 H), 7.36 – 7.41
(m, 1 H), 7.51 – 7.64 (comp, 7 H), 7.78 – 7.82 (comp, 2 H), 8.14 (d, J = 2.1 Hz, 1 H), 8.59 (d, J
= 2.1 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 101.9, 121.4, 121.6, 123.9, 126.4, 127.2, 128.8,
128.9, 129.2, 129.4, 132.0, 138.3 (2 C), 142.5, 147.1; HRMS: (ESI, m/z) calcd for
C19H13BrN2Na [M+Na]+ 371.0160, observed 371.0164.
5-(4-fluorophenyl)-1-phenyl-1H-pyrrolo[2,3-b]pyridine (1z): Yield: 92%; colourless
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solid; mp: 121 – 123 C; H NMR: (300 MHz, CDCl3) δ 6.70 (d, J = 3.6 Hz, 1 H), 7.16 – 7.22
(comp, 2 H), 7.38 (app t, J = 7.2 Hz, 1 H), 7.54 – 7.63 (comp, 6 H), 7.79 – 7.82 (comp, 2 H),
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8.12 (d, J = 2.1 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 101.8, 115.8 (d, JF−C = 21.3 Hz),
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121.5, 123.9, 126.4, 127.3, 128.7, 128.9 (d, JF−C = 8.0 Hz), 129.5 (d, JF−C = 12.9 Hz), 129.4,
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135.5, 138.3, 142.7, 146.9, 162.4 (d, JF−C = 245.1 Hz); HRMS: (ESI, m/z) calcd for
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C19H13FN2Na [M+Na]+ 311.0960, observed 311.0956.
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1-phenyl-5-(pyren-1-yl)-1H-pyrrolo[2,3-b]pyridine (1aa): Yield: 91%; green solid; mp:
130 – 132οC; 1H NMR: (300 MHz, CDCl3) δ 6.76 (d, J = 3.6 Hz, 1 H), 7.39 (app t, J = 7.5 Hz, 1
H), 7.56 – 7.62 (comp, 2 H), 7.65 (d, J = 3.6 Hz, 1 H), 7.86 – 7.89 (comp, 2 H), 8.00 – 8.06
(comp, 3 H), 8.13 (comp, 2 H), 8.17 – 8.28 (comp, 5 H), 8.65 (d, J = 2.1 Hz, 1 H); 13C NMR: (75
MHz, CDCl3) δ 101.8, 121.3, 123.9, 124.6, 124.8 (2 C), 124.9, 125.0, 125.1, 126.0, 126.4, 127.3,
127.4, 127.6, 128.1, 128.6, 129.0, 129.4, 129.9, 130.6 (2 C), 130.9, 131.4, 135.1, 138.4, 145.3,
146.7; HRMS: (ESI, m/z) calcd for C29H19N2 [M+H]+ 395.1548, observed 395.1545.
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General procedure for cyanation:
(0.2 mmol scale):
To an oven dried 10 mL schlenk tube 38.8 mg (0.2 mmol) of 1ꢀphenylꢀ1Hꢀpyrrolo[2,3ꢀ
b]pyridine (1a) was taken. To that NCTS (109 mg, 0.4 mmol), NaOAc (8.2 mg, 50 mol%),
AgOTf (15.4 mg, 30 mol%) and [RuCl2(pꢀcymene)]2 (6.1 mg, 5 mol%) were added. Next it was
degassed and backfilled with nitrogen. 2.0 mL of anhydrous DCE was added as solvent. Then
the tube was degassed and backfilled with nitrogen (3 times). The tube was closed with a teflonꢀ
ο
lined cap and heated at 110 C (oil bath temperature). After 30 h, the reaction was stopped and
cooled to room temperature. The reaction mixture was filtered through a short pad of celite and
concentrated under vacuo. The crude reaction mixture was directly purified by column
chromatography on silica gel using pet ether/ethyl acetate as eluent and isolated the product 3a in
84 % yield (36.8 mg).
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(Gram scale):
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1 gram (5.1 mmol) of 1ꢀphenylꢀ1Hꢀpyrrolo[2,3ꢀb]pyridine (1a) was taken in an oven
dried 100 mL round bottom flask equipped with a reflux condenser. To that NCTS (2.8 g, 10.3
mmol), NaOAc (205 mg, 50 mol%), AgOTf (385 mg, 30 mol%) and [RuCl2(pꢀcymene)]2 (154
mg, 5 mol%) were added. Next it was degassed and backfilled with nitrogen. 50 mL of
anhydrous DCE was added. Then it was degassed and backfilled with nitrogen (3 times) and
heated at 110 οC (oil bath temperature). After 30 h, the reaction was stopped and cooled to room
temperature. The reaction mixture was filtered through a short pad of celite and concentrated
under vacuo. The crude reaction mixture was directly purified by column chromatography on
silica gel using pet ether/ethyl acetate as eluent to give 2ꢀ(1Hꢀpyrrolo[2,3ꢀb]pyridinꢀ1ꢀ
yl)benzonitrile (2a) (0.79 g, 70% yield).
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Characterization data of cyanated products:
2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3a): Yield: 84% (36.8 mg); colourless
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solid; mp: 132 – 133 C; 1H NMR: (600 MHz, CDCl3) δ 6.75 (d, J = 3.6 Hz, 1 H), 7.21 (dd, J =
7.8 Hz, 4.8 Hz, 1 H), 7.53 (td, J = 7.2 Hz, J = 1.2 Hz, 1 H), 7.58 (d, J = 3.6 Hz, 1 H), 7.78 – 7.83
(comp, 2 H), 7.87 (dd, J = 7.8 Hz, 1.2 Hz), 8.03 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 8.39 (dd, J = 4.8
Hz, 1.8 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 102.8, 110.0, 116.7, 117.5, 121.3, 127.5,
128.1, 128.3, 129.5, 133.7, 134.2, 140.4, 143.9, 147.8; HRMS: (ESI, m/z) calcd for C14H9N3Na
[M+Na]+ 242.0694, observed 242.0687.
4-methyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3b): Yield: 81% (37.7 mg); pale
orange solid; mp: 88 − 89 οC; 1H NMR: (300 MHz, CDCl3) δ 2.51 (s, 3 H), 6.70 (d, J = 3.6 Hz, 1
H), 7.18 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.30 (dd, J = 8.4 Hz, 1.5 Hz, 1 H), 7.52 (d, J = 3.6 Hz, 1
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(dd, J = 4.8 Hz, 1.5 Hz, 1 H); C NMR: (150 MHz, CDCl3) δ 21.9, 102.6, 107.1, 116.9, 117.3,
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121.2, 128.4, 128.5, 128.8, 129.4, 113.8, 140.3, 143.8, 145.1, 147.8; HRMS: (EI, m/z) calcd for
C15H11N3 [M]+ 233.0953, observed 233.0948.
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4-(dimethylamino)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3c): Yield: 83% (43.5
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mg); colourless solid; mp: 179 – 180 C; H NMR: (600 MHz, CDCl3) δ 3.10 (s, 6 H), 6.70 –
6.72 (comp, 2 H), 6.95 (d, J = 3.0 Hz, 1 H), 7.18 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.57 (d, J = 3.6
Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 8.01 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.38 (dd, J = 4.8 Hz, 1.8
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Hz, 1 H); C NMR: (150 MHz, CDCl3) δ 40.0, 95.1, 102.0, 110.4, 110.5, 117.0, 118.4, 121.2,
128.7, 129.2, 134.8, 141.6, 143.7, 147.9, 153.1; HRMS: (EI, m/z) calcd for C16H14N4 [M]+
262.1218, observed 262.1212.
4-methoxy-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3d): Yield: 80% (39.9 mg);
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pale yellow solid; mp: 132 − 135 C; H NMR: (600 MHz, CDCl3) δ 3.93 (s, 3 H), 6.73 (d, J =
3.6 Hz, 1 H), 7.02 (dd, J = 9.0 Hz, 2.4 Hz, 1 H), 7.21 (dd, J = 9.0 Hz, 2.4 Hz, 1 H), 7.21 (dd, J =
7.8 Hz, 4.8 Hz, 1 H), 7.34 (d, J = 2.4 Hz, 1 H), 7.58 (d, J = 4.2 Hz, 1 H), 7.76 (d, J = 9.0 Hz, 1
H), 8.02 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.39 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); 13C NMR: (150 MHz,
CDCl3) δ 55.9, 101.4, 102.7, 113.6, 113.8, 117.1, 117.4, 121.3, 128.3, 129.4, 135.3, 142.1, 143.9,
147.7, 163.4; HRMS: (EI, m/z) calcd for C15H11N3O [M]+ 249.0902, observed 249.0908.
2,4-dimethoxy-6-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3e): Yield: 75% (41.9 mg);
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colourless solid; mp: 141 − 143 C; H NMR: (600 MHz, CDCl3) δ 3.92 (s, 3 H), 3.98 (s, 3 H),
6.52 (d, J = 1.8 Hz, 1 H), 6.70 (d, J = 3.6 Hz, 1 H), 6.92 (dd, J = 1.8 Hz, 1 H), 7.19 (dd, J = 7.8
Hz, 4.8 Hz, 1 H), 7.57 (d, J = 4.2 Hz, 1 H), 8.00 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.38 (dd, J = 4.8
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Hz, 1.2 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 55.9, 56.4, 92.2, 97.3, 102.5, 105.2, 114.6,
117.3, 121.4, 128.4, 129.4, 143.0, 143.8, 147.8, 163.7, 164.4; HRMS: (ESI, m/z) calcd for
C16H13O2N3Na [M+Na]+ 302.0905, observed 302.0901.
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3-methoxy-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3f): Yield: 87% (43.3 mg);
grey solid; mp: 140 − 143 οC; 1H NMR: (600 MHz, CDCl3) δ 3.79 (s, 3 H), 6.73 (d, J = 3.6 Hz, 1
H), 7.17 (dd, J = 8.4 Hz, 4.2 Hz, 1 H), 7.32 – 7.34 (comp, 2 H), 7.44 (dd, J = 8.4 Hz, 1.8 Hz, 1
H), 7.54 (t, J = 8.4 Hz, 1 H), 8.01 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.36 (dd, J = 4.2 Hz, 1.2 Hz, 1
H); 13C NMR: (150 MHz, CDCl3) δ 56.2, 102.2, 114.0, 116.0, 116.8, 116.9, 120.6, 124.9, 129.0,
129.2, 129.3, 129.9, 143.7, 148.3, 156.1; HRMS: (EI, m/z) calcd for C15H11N3O [M]+ 249.0902,
observed 249.0896.
3-methyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3g): Yield: 41% (19.1 mg);
yellow solid; mp: 86 – 89 οC; 1H NMR: (600 MHz, CDCl3) δ 2.11 (s, 3 H), 6.77 (d, J = 4.2 Hz, 1
H), 7.18 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.31 (d, J = 3.6 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 7.65
(app d, J = 7.2 Hz, 1 H), 7.69 (app d, J = 7.8 Hz, 1 H), 8.04 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 8.35
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(dd, J = 4.2 Hz, 1.2 Hz, 1 H); C NMR: (150 MHz, CDCl3) δ 18.0, 102.6, 113.3, 116.3, 116.9,
120.6, 128.1, 129.0, 129.5, 131.3, 135.6, 138.9, 139.4, 144.0, 148.0; HRMS: (EI, m/z) calcd for
C15H11N3 [M]+ 233.0953, observed 233.0944.
3-acetyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3h): Yield: 51% (26.6 mg);
brown solid; mp: 86 – 88 οC; 1H NMR: (600 MHz, CDCl3) δ 1.92 (s, 3 H), 6.50 (d, J = 3.6 Hz, 1
H), 7.21 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.44 (d, J = 3.6 Hz, 1 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.98
(dd, J = 7.2 Hz, 1.8 Hz, 1 H), 8.00 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.04 (dd,J = 7.2 Hz, 1.2 Hz, 1
H), 8.34 (dd, J = 4.8 Hz, 1.2 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 28.1, 103.7, 113.3, 115.7,
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117.6, 120.8, 128.3, 128.8, 129.8, 133.2, 136.3, 138.1, 139.7, 144.2, 148.3, 198.4; HRMS: (EI,
m/z) calcd for C16H11N3O [M]+ 261.0902, observed 261.0902.
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methyl 3-cyano-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate (3i): Yield: 66% (36.6 mg);
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colourless solid; mp: 92 – 94 C; H NMR: (300 MHz, CDCl3) δ 3.41 (s, 3 H), 6.76 (d, J = 3.6
Hz, 1 H), 7.15 (dd, J = 7.8 Hz, 1.8 Hz, 1 H), 7.45 (d, J = 3.6 Hz, 1 H), 7.64 (t, J = 7.8 Hz, 1 H),
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7.98 (app t, J = 2.1 Hz, 1 H), 8.01 (app t, J = 2.1 Hz, 1 H), 8.23 – 8.29 (comp, 2 H); C NMR:
(150 MHz, CDCl3) δ 52.5, 102.9, 113.5, 115.7, 117.2, 120.9, 128.5 (2 C), 131.2, 135.4, 136.9,
139.8, 143.7, 148.7, 164.9; HRMS: (EI, m/z) calcd for C16H11N3O2 [M]+ 277.0859, observed
277.0852.
5-methoxy-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3j): Yield: 60% (29.9 mg);
colourless solid; mp: 130 − 133 οC; 1H NMR: (600 MHz, CDCl3) δ 3.92 (s, 3 H), 6.71 (d, J = 3.6
Hz, 1 H), 7.19 (dd, J = 8.4 Hz, 4.8 Hz, 1 H), 7.29 – 7.32 (comp, 2 H), 7.49 (d, J = 3.6 Hz, 1 H),
7.65 (d, J = 8.4 Hz, 1 H), 8.02 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 8.37 (dd, J = 4.8 Hz, 1.8 Hz, 1 H);
13C NMR: (150 MHz, CDCl3) δ 56.0, 102.3, 111.2, 116.4, 117.1, 118.0, 120.1, 121.0, 128.5,
129.3, 129.6, 133.4, 143.8, 148.1, 158.5; HRMS: (ESI, m/z) calcd for C15H11N3ONa [M+Na]+
272.0800, observed 272.0811.
5-methyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3k): Yield: 66% (30.7 mg);
colourless solid; mp: 143 – 146 οC; 1H NMR: (600 MHz, CDCl3) δ 2.49 (s, 3 H), 6.72 (d, J = 4.2
Hz, 1 H), 7.19 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.54 (d, J = 3.6 Hz, 1 H), 7.58 (dd, J = 8.4 Hz, 1.8
Hz, 1 H), 7.66 – 7.68 (comp, 2 H), 8.02 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 8.38 (dd, J = 4.2 Hz, 1.2
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233.0953, observed 233.0948.
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5-(tert-butyl)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3l): Yield: 80% (44.0 mg);
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colourless gummy; H NMR: (300 MHz, CDCl3) δ 1.38 (s, 9 H), 6.70 (d, J = 3.6 Hz, 1 H), 7.17
(dd, J = 8.1 Hz, 4.8 Hz, 1 H), 7.52 (d, J = 3.6 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.76 – 7.83
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(comp, 2 H), 8.00 (dd, J = 7.8 Hz, 1.8 Hz, 1 H), 8.36 (dd, J = 4.8 Hz, 1.5 Hz, 1 H); C NMR:
(150 MHz, CDCl3) δ 31.0, 34.8, 102.5, 109.5, 117.2, 117.3, 121.2, 127.6, 128.4, 129.4, 131.1,
131.2, 137.8, 143.8, 147.8, 151.0; HRMS: (ESI, m/z) calcd for C18H17N3Na [M+Na]+ 298.1320,
observed 298.1308.
4-(1H-pyrrolo[2,3-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carbonitrile (3m): Yield: 75% (44.3
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mg); colourless solid; mp: 150 − 153 C; H NMR: (600 MHz, CDCl3) δ 6.77 (d, J = 3.6 Hz, 1
H), 7.23 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.48 (app t, J = 7.2 Hz, 1 H), 7.53 – 7.55 (comp, 2 H),
7.62 – 7.65 (comp, 3 H), 7.89 (d, J = 8.4 Hz, 1 H), 7.99 (dd, J = 8.4 Hz, 2.4 Hz, 1 H), 8.04 – 8.06
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(comp, 2 H), 8.42 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); C NMR: (150 MHz, CDCl3) δ 102.9, 110.2,
116.7, 117.5, 121.3, 127.1, 128.2, 128.4, 128.5, 129.2, 129.5, 132.3, 132.5, 138.2, 139.2, 140.9,
143.9, 147.9; HRMS: (EI, m/z) calcd for C20H13N3 [M]+ 295.1109, observed 295.1104.
5-(dimethylamino)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3n): Yield: 34% (17.8
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mg); brown solid; mp: 189 − 191 C; H NMR: (600 MHz, CDCl3) δ 3.07 (s, 6 H), 6.68 (d, J =
3.6 Hz, 1 H), 7.02 – 7.04 (comp, 2 H), 7.16 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.46 (d, J = 3.6 Hz, 1
H), 7.52 (dd, J = 7.2 Hz, 2.4 Hz, 1 H), 8.00 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 8.37 (dd, J = 4.8 Hz,
1.8 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 40.3, 101.6, 111.2, 115.7, 116.7, 116.8, 117.2,
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262.1218, observed 262.1213.
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colourless solid; mp: 156 − 158 οC; 1H NMR: (600 MHz, CDCl3) δ 4.02 (s, 3 H), 6.79 (d, J = 3.6
Hz, 1 H), 7.25 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.66 (d, J = 4.2 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H),
8.04 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.40 (dd, J = 4.8 Hz, 1.8 Hz, 1 H), 8.42 (dd, J = 8.4 Hz, 1.8
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Hz, 1 H), 8.54 (d, J = 1.8 Hz, 1 H); C NMR: (150 MHz, CDCl3) δ 52.8, 103.8, 109.2, 116.2,
118.0, 121.6, 127.7 (2 C), 128.9, 129.6, 134.5, 135.7, 143.6, 144.0, 147.7, 164.6; HRMS: (EI,
m/z) calcd for C16H11N3O2 [M]+ 277.0851, observed 277.0847.
5-acetyl-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3p): Yield: 44% (23 mg); pale
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orange solid; mp: 145 − 145 C; H NMR: (600 MHz, CDCl3) δ 2.70 (s, 3 H), 6.79 (d, J = 3.6
Hz, 1 H), 7.25 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.66 (d, J = 4.2 Hz, 1 H), 8.03 – 8.06 (comp, 2 H),
8.34 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.40 (dd, J = 4.2 Hz, 1.2 Hz, 1 H), 8.44 (d, J = 2.4 Hz, 1 H);
13C NMR: (150 MHz, CDCl3) δ 26.6, 103.9, 109.3, 116.2, 118.0, 121.6, 127.7, 127.9, 129.7,
133.1, 134.6, 135.2, 143.6, 144.0, 147.7, 194.9; HRMS: (EI, m/z) calcd for C16H11N3O [M]+
261.0902, observed 261.0908.
1-(1H-pyrrolo[2,3-b]pyridin-1-yl)-2-naphthonitrile (3q): Yield: 78% (42 mg); colourless
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solid; mp 151 − 152 C (crystallization from diethyl ether and pet ether); H NMR: (600 MHz,
CDCl3) δ 6.87 (d, J = 3.6 Hz, 1 H), 7.22 (dd, J = 8.4 Hz, 4.8 Hz, 1 H), 7.39 (dd, J = 8.4 Hz, 1.2
Hz, 1 H), 7.47 (d, J = 3.6 Hz, 1 H), 7.54 (ddd, J = 8.4 Hz, 7.2 Hz, 1.2 Hz, 1 H), 7.69 (ddd, J =
8.4 Hz, 7.2 Hz, 1.2 Hz, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 8.08 (d, J = 8.4
Hz, 1 H), 8.10 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 8.33 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); 13C NMR: (150
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MHz, CDCl3) δ 102.9, 110.4, 116.6, 117.2, 120.6, 124.2, 126.7, 128.4, 128.6, 129.3, 129.5,
129.6, 129.7, 130.8, 135.8, 139.8, 144.2, 149.1; HRMS: (ESI, m/z) calcd for C18H11N3Na
[M+Na]+ 292.0851, observed 292.0837.
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3-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzo[b]thiophene-2-carbonitrile (3r): Yield: 78% (43
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mg); yellow solid; mp: 136 – 137 C; H NMR: (300 MHz, CDCl3) δ 6.81 (d, J = 3.6 Hz, 1 H),
7.22 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 7.46 (app t, J = 7.5 Hz, 1 H), 7.54 (d, J = 3.6 Hz, 1 H), 7.60
(m, 1 H), 7.67 (app d, J = 8.4 Hz, 1 H), 7.90 (app d, J = 8.1 Hz, 1 H), 8.05 (dd, J = 7.8 Hz, 1.5
Hz, 1 H), 8.37 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 103.7, 104.3, 113.0,
117.7, 121.1, 123.0, 124.3, 125.9, 128.2, 128.7, 129.6, 133.3, 139.6, 140.1, 144.1, 147.8; HRMS:
(EI, m/z) calcd for C16H9N3S [M]+ 275.0517, observed 275.0520.
2-(1H-pyrrolo[2,3-b]pyridin-1-yl)thiophene-3-carbonitrile (3s): Yield: 87% (39.2 mg);
colourless solid; mp: 90 − 92 οC; 1H NMR: (600 MHz, CDCl3) δ 6.75 (d, J = 3.6 Hz, 1 H), 7.19 –
7.21 (comp, 2 H), 7.24 (dd, J = 7.8 Hz, 4.8 Hz, 1 H), 8.00 (dd, J = 7.2 Hz, 1.8 Hz, 1 H), 8.02 (d,
J = 4.2 Hz, 1 H), 8.44 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 99.4, 104.4,
115.1, 118.2, 121.4, 121.5, 126.7, 127.1, 129.6, 143.9, 147.1, 147.8; HRMS: (ESI, m/z) calcd for
C12H8N3S [M+H]+ 226.0439, observed 226.0435.
2-(1H-pyrrolo[2,3-b]pyridin-1-yl)furan-3-carbonitrile (3t): Yield: 64% (26.7 mg); brown
solid; mp: 62 − 64 οC; 1H NMR: (600 MHz, CDCl3) δ 6.76 – 6.78 (comp, 2 H), 7.26 (dd, J = 7.8
Hz, 4.8 Hz, 1 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.58 (d, J = 3.6 Hz, 1 H), 8.00 (dd, J = 8.4 Hz, 1.2
Hz, 1 H), 8.49 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 86.1, 105.2, 112.8,
112.9, 118.5, 121.3, 126.0, 129.7, 139.4, 144.7, 147.3, 150.4; HRMS: (EI, m/z) calcd for
C12H7N3O [M]+ 209.0589, observed 209.0583.
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3-(1H-pyrrolo[2,3-b]pyridin-1-yl)furan-2-carbonitrile (3u): Yield: 39% (16.4 mg); pale
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yellow solid; mp: 133 – 135 C; H NMR: (600 MHz, CDCl3) δ 6.75 (d, J = 3.6 Hz, 1 H), 7.23
(dd, J = 8.4 Hz, 4.2 Hz, 1 H), 7.65 (d, J = 1.8 Hz, 1 H), 7.77 (d, J = 2.4 Hz, 1 H), 7.82 (d, J = 4.2
Hz, 1 H), 8.00 (dd, J = 7.2 Hz, 1.8 Hz, 1 H), 8.43 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); 13C NMR: (150
MHz, CDCl3) δ 104.6, 108.5, 112.0, 115.5, 117.9, 121.4, 125.6, 129.5, 136.0, 144.1, 147.2,
147.6; HRMS: (ESI, m/z) calcd for C12H8N3O [M+H]+ 210.0667, observed 210.0663.
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2-(4-phenyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3v): Yield: 50% (29.5 mg);
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yellow solid; mp: 223 − 225 C; H NMR: (600 MHz, CDCl3) δ 6.94 (d, J = 3.6 Hz, 1 H), 7.30
(d, J = 4.8 Hz, 1 H), 7.49 – 7.59 (comp, 4 H), 7.62 (d, J = 4.2 Hz, 1 H), 7.78 – 7.85 (comp, 4 H),
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7.89 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 8.45 (d, J = 4.8 Hz, 1 H); C NMR: (150 MHz, CDCl3) δ
102.3, 110.1, 116.6, 116.7, 119.3, 127.6, 128.2, 128.4, 128.5, 128.6, 128.9, 133.7, 134.2, 138.4,
140.5, 142.9, 144.2, 148.4; HRMS: (EI, m/z) calcd for C20H13N3 [M]+ 295.1109, observed
295.1112.
2-(4-(m-tolyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3w): Yield: 75% (46.4 mg);
colourless solid; mp: 143 − 145 οC; 1H NMR: (600 MHz, CDCl3) δ 2.51 (s, 3 H), 6.94 (d, J = 3.6
Hz, 1 H), 7.29 (t, J = 2.4 Hz, 1 H), 7.32 (app d, J = 7.2 Hz, 1 H), 7.47 (app t, J = 7.2 Hz, 1 H),
7.54 (td, J = 7.2 Hz, 1.2 Hz, 1 H), 7.58 – 7.60 (comp, 2 H), 7.61 (d, J = 3.6 Hz, 1 H), 7.80 – 7.86
(comp, 2 H), 7.89 (dd, J = 4.8 Hz, 1.8 Hz, 1 H), 8.43 (d, J = 4.8 Hz, 1 H); 13C NMR: (150 MHz,
CDCl3) δ 21.5, 102.4, 110.1, 116.6, 116.7, 119.3, 125.7, 127.6, 128.2, 128.3, 128.8, 129.2, 129.3,
133.7, 134.2, 138.3, 138.6, 140.6, 143.1, 144.2, 148.4; HRMS: (EI, m/z) calcd for C21H15N3
[M]+ 309.1266, observed 309.1251.
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2-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3x): Yield: 79% (43.6 mg);
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colourless solid; mp: 142 − 143 C; H NMR: (600 MHz, CDCl3) δ 6.80 (d, J = 4.2 Hz, 1 H),
7.42 (app t, J = 7.2 Hz, 1 H), 7.51 – 7.56 (comp, 3 H), 7.62 (d, J = 3.6 Hz, 1 H), 7.66 – 7.67
(comp, 2 H), 7.82 (td, J = 7.8 Hz, 1.8 Hz, 1 H), 7.86 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 7.89 (dd, J =
7.2 Hz, 1.8 Hz, 1 H), 8.21 (d, J = 2.4 Hz, 1 H), 8.62 (d, J = 1.8 Hz, 1 H); 13C NMR: (150 MHz,
CDCl3) δ 103.1, 109.9, 116.7, 121.3, 127.2, 127.4, 127.6, 127.9, 128.1, 129.0 (2 C), 131.3,
133.8, 134.2, 139.1, 140.4, 143.2, 147.3; HRMS: (EI, m/z) calcd for C20H13N3 [M]+ 295.1109,
observed 295.1110.
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2-(5-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3y): Yield: 88% (65.9 mg);
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colourless solid; mp: 208 – 210 C; H NMR: (300 MHz, CDCl3) δ 6.78 (d, J = 3.6 Hz, 1 H),
7.48 – 7.56 (comp, 3 H), 7.59 – 7.63 (comp, 3 H), 7.79 – 7.81 (comp, 2 H), 7.87 (dd, J = 7.2 Hz,
1.8 Hz, 1 H), 8.14 (d, J = 2.1 Hz, 1 H), 8.54 (d, J = 2.1 Hz, 1 H); 13C NMR: (150 MHz, CDCl3)
δ 103.1, 110.0, 116.6, 121.3, 121.6, 127.7 (2 C), 128.1, 129.0, 129.2, 130.1, 133.8, 134.2, 138.0,
140.2, 142.9, 147.4; HRMS: (EI, m/z) calcd for C20H12N3Br [M]+ 373.0215, observed 373.0216.
2-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3z): Yield: 75% (47 mg);
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colourless solid; mp: 181 – 183 C; H NMR: (600 MHz, CDCl3) δ 6.79 (d, J = 3.6 Hz, 1 H),
7.19 – 7.22 (comp, 2 H), 7.55 (td, J = 7.2 Hz, 1.8 Hz, 1 H), 7.59 – 7.62 (comp, 3 H), 7.89 (dd, J
= 7.2 Hz, 1.8 Hz, 1 H), 8.15 (d, J = 2.4 Hz, 1 H), 8.56 (d, J = 2.4 Hz, 1 H); 13C NMR: (150 MHz,
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CDCl3) δ 103.0, 110.0, 115.9 (d, JF−C = 21.3 Hz), 116.7, 121.2, 127.7 (2 C), 128.1, 129.0 (d,
3JF−C = 8.0 Hz), 129.1, 130.4, 133.7, 134.0, 135.2 (d, JF−C = 3.4 Hz), 140.3, 143.0, 147.3, 162.4
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(d, 1JF−C = 245.0 Hz); HRMS: (EI, m/z) calcd for C20H12N3F [M]+ 313.1015, observed 313.1014.
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2-(5-(pyren-1-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3aa): Yield: 51% (42.8 mg);
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yellow solid; mp: 225 – 227 C; H NMR: (300 MHz, CDCl3) δ 6.86 (d, J = 3.6 Hz, 1 H), 7.56
(td, J = 7.5 Hz, 1.5 Hz, 1 H), 7.69 (d, J = 3.9 Hz, 1 H), 7.84 (td, J = 7.8 Hz, 1.5 Hz, 1 H), 7.90 –
7.95 (comp, 2 H), 8.01 – 8.07 (comp, 3 H), 8.13 (comp, 2 H), 8.18 – 8.29 (comp, 5 H), 8.63 (d, J
= 2.1 Hz, 1 H); 13C NMR: (150 MHz, CDCl3) δ 103.0, 110.0, 116.8, 121.0, 124.7, 124.8, 124.9,
125.2, 126.1, 127.4, 127.6, 127.7, 127.8, 128.2 (2 C), 129.1 (2 C), 130.8, 130.9 (2 C), 131.1,
131.4, 133.8, 134.2, 134.8, 140.4, 145.6, 147.2; HRMS: (EI, m/z) calcd for C30H17N3 [M]+
419.1422, observed 419.1424.
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2-(3-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3ab): Yield: 67% (40 mg);
colourless solid; mp: 214 − 215 οC; 1H NMR: (600 MHz, CDCl3) δ 7.30 (dd, J = 7.8 Hz, 4.8 Hz,
1 H), 7.56 (td, J = 7.2 Hz, 1.2 Hz, 1 H), 7.60 (s, 1H), 9.73 (dd, J = 7.8 Hz, 1.2 Hz, 1 H), 7.80 (td,
J = 7.8 Hz, 1.2 Hz, 1 H), 7.88 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.00 (dd, J = 8.4 Hz, 1.8 Hz, 1 H),
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8.43 (dd, J = 4.8 Hz, 1.2 Hz, 1 H); C NMR: (150 MHz, CDCl3) δ 92.3, 110.3, 116.3, 118.1,
120.7, 127.0, 128.1 (2 C), 128.3, 133.8, 134.2, 139.4, 145.1, 146.8; HRMS: (EI, m/z) calcd for
C14H8BrN3 [M]+ 296.9902, observed 296.9889.
2-(3-iodo-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (3ac): Yield: 83% (57.3 mg);
colourless solid; mp: 219 − 221 οC; 1H NMR: (600 MHz, CDCl3) δ 7.30 (dd, J = 7.8 Hz, 4.8 Hz,
1 H), 7.55 – 7.58 (m, 1 H), 7.73 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.78 – 7.81 (m, 1 H), 7.86 (dd, J =
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8.4 Hz, 1.2 Hz, 1 H), 7.88 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 8.40 (dd, J = 4.8 Hz, 1.8 Hz, 1 H); C
NMR: (150 MHz, CDCl3) δ 58.1, 110.3, 116.3, 118.2, 123.7, 128.1 (2 C), 130.0, 131.9, 133.8,
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