Palladium-catalysed cross-coupling as a key step in the synthesis of pyridyl-benzamides, -benzylamines and -sulfonamides

Article abstract of DOI:10.1016/j.tet.2016.11.071

Novel N-, O- and S-substituted pyridyl-benzamides, -benzylamines and -sulfonamides were prepared by means of palladium-catalysed cross-coupling reactions. The synthetic approach, using Pd₂(dba)₃as palladium source and rac-BINAP as supporting ligand, proved to be successful for C[sbnd]N, C[sbnd]O and C[sbnd]S cross-coupling reactions. One of the substrates underwent an unexpected nucleophilic aromatic substitution of fluorine, rather than the expected C[sbnd]N cross-coupling reaction.

Full text of DOI:10.1016/j.tet.2016.11.071

Accepted Manuscript
Palladium-catalysed cross-coupling as a key step in the synthesis of pyridyl-
benzamides, -benzylamines and -sulfonamides
Charles R.K. Changunda, Adriaan E. Basson, Sandy F. van Vuuren, Amanda L.
Rousseau, Moira L. Bode
PII:
S0040-4020(16)31251-0
10.1016/j.tet.2016.11.071
TET 28285
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 August 2016
Revised Date: 15 November 2016
Accepted Date: 28 November 2016
Please cite this article as: Changunda CRK, Basson AE, van Vuuren SF, Rousseau AL, Bode ML,
Palladium-catalysed cross-coupling as a key step in the synthesis of pyridyl-benzamides, -benzylamines
and -sulfonamides, Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.071.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Palladium-catalysed cross-coupling as a key step in the synthesis of pyridyl-benzamides,
-benzylamines and -sulfonamides.
Charles R. K. Changunda,1 Adriaan E. Basson,2 Sandy F. van Vuuren,3 Amanda L.
Rousseau1 and Moira L. Bode1*
1Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS,
2050, South Africa
2Centre for HIV and STI: HIV Virology Section, National Institute of Communicable Diseases, 1
Modderfontein Road, Sandringham, 2141, South Africa
3Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7
York Road, Parktown, 2193, South Africa
*Corresponding author: Moira.Bode@wits.ac.za
Graphical Abstract
1

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Palladium-catalysed cross-coupling as a key step in the synthesis of pyridyl-benzamides,
-benzylamines and -sulfonamides.
Charles R. K. Changunda,1 Adriaan E. Basson,2 Sandy F. van Vuuren,3 Amanda L.
Rousseau1 and Moira L. Bode1*
1Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS,
2050, South Africa
2Centre for HIV and STI: HIV Virology Section, National Institute of Communicable Diseases, 1
Modderfontein Road, Sandringham, 2141, South Africa
3Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7
York Road, Parktown, 2193, South Africa
Abstract
Novel N-, O- and S-substituted pyridyl-benzamides, -benzylamines and -sulfonamides were
prepared by means of palladium-catalysed cross-coupling reactions. The synthetic approach,
using Pd2(dba)3 as palladium source and rac-BINAP as supporting ligand, proved to be
successful for C-N, C-O and C-S cross-coupling reactions. One of the substrates underwent
an unexpected nucleophilic aromatic substitution of fluorine, rather than the expected C-N
cross-coupling reaction.
Keywords
NNRTI; pyridylbenzamide; palladium-catalysed cross-coupling
1. Introduction
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs used in first-line
treatment regimens the world over. One of their main advantages is related to their high
selectivity which results in relatively low toxicity compared to other drug classes.1 However,
their effectiveness is threatened by development of drug resistance; and new members of this
drug class are constantly being sought.2 As these drugs are used for long-term therapy, their
side-effect profiles are extremely important and drugs with reduced side-effects are highly
desirable.3
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NNRTIs act by binding to a hydrophobic site situated 10 Å from the catalytic site in HIV-1
reverse transcriptase. This binding leads to a conformational change in the catalytic site that
slows down or halts polymerase activity.4 The original FDA-approved NNRTIs delavirdine
(1) and nevirapine (2) have a low tolerance to changes in the amino acids lining the allosteric
site (Fig. 1). Thus, mutation at even a single position can lead to these drugs losing affinity
for the site and therefore losing efficacy.5 The subsequently approved NNRTI efavirenz (3)
proved more resilient to the effects of single-point mutations, still maintaining some
(although reduced) activity in certain cases and full activity in others.6 However, when faced
with more than one mutation, efavirenz loses all activity. The newest NNRTIs etravirine (4)
and rilpivirine (5) are able to maintain almost full activity against a range of clinically
important mutants,6
although evidence of resistance is now being seen.7 These compounds
have multiple possible binding modes in the allosteric site and, when encountering a modified
amino acid, they are able to adopt an alternative binding mode and maintain significant
binding affinity.8
Fig. 1 FDA-approved NNRTIs
Our earlier efforts towards finding compounds acting as NNRTIs against HIV-1 led to the
identification of imidazo[1,2-a]pyridines such as 6 (Fig. 2), which exhibited activity
comparable to that of nevirapine (2) in a whole-cell anti-HIV assay.9
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Fig. 2
Using the structure of compounds such as 6 as a starting point, we wanted to design
alternative scaffolds with NNRTI activity, but which inherently possessed greater flexibility.
Using a scaffold-hopping approach10 and applying a “virtual ring-opening” to the imidazole
ring of compound 6 by “cleaving” the pyridyl N-C bond gave rise to pyridyl-benzamide
scaffold 7 (Fig.2, R=Cl, R1=c-hex, R2=H) as the initial target for synthesis. As a compound
class, pyridyl-benzamides are of interest in medicinal chemistry as a result of activity against
a number of targets. For example, they are active at the human neuronal nicotinic receptors11
and act as anti-parasitic12 and antibacterial agents.13
Fig. 3
It was envisaged that the second target – the corresponding reduced pyridyl-benzylamine
derivatives 8 (Fig. 3) – would be more flexible, and thus might better maintain activity
against viral mutants. The final scaffold envisaged for synthesis was pyridyl-sulfonamide
scaffold 9. Sulfonamides are privileged motifs in biological systems, with many compounds
in this class displaying biological activity.14,15 All three targets appeared amenable to a
similar synthetic approach.
2. Results and discussion
Scaffold 7 was accessed via activation of the carboxylic acid 10 to form a reactive acyl
chloride which was subsequently aminated with 2-amino-6-bromopyridine 11 to give
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benzamide derivatives 12 (Scheme 1). A copper-mediated protocol was initially used for
nucleophilic displacement of the pyridyl halide with selected primary amines.16,17 Moderate
success was achieved for the aniline, benzylamine and cyclohexylamine nucleophiles.
However, similar reactions to cross-couple secondary amines to compound 12 were
unsuccessful even after prolonged reaction times at moderately high temperatures of 120°C.
A three-fold scaling up of the catalyst loading from 5 to 15 mol% proved ineffective, as did a
change of the base (from K3PO4 to KOtBu or K2CO3) or solvent (toluene, DMF or THF). In
most cases more than 90% of the starting material was recovered. An alternative palladium
(Pd)-mediated protocol, employing tris-dibenzylideneacetone di-palladium [Pd2(dba)3] as
pre-catalyst with (rac)-BINAP as supporting ligand, was tested. The choice of supporting
ligand was based on the findings of Buchwald et al. that BINAP was the most generally
successful ligand for cross-coupling of amines with aryl, and in particular, heteroaryl
bromides.18,19,20 The bulky rac-BINAP supporting ligand (with a cone angle of 91°) appears
to stabilise the palladium catalyst system and obviates unwanted side reactions, resulting in
favourable product yields. This approach proved versatile in effecting the desired cross-
coupling reactions to yield products 7a-i (Scheme 1).
7a R= o-Cl, R1= c-hex, R2= H, 75% (79%)a; 7b R= o-Cl, R1= CH2Ph, R2= H, 62% (25%)a;
7c R= o-Cl, R1= Ph, R2=H, 65% (43%)a; 7d R= o-Cl, R1,R2=
, 56%;
7e R= o-Cl, R1,R2=
7g R= m-Cl, R1,R2=
7i R= p-CN, R1,R2=
, 68%; 7f R= H, R1,R2=
, 52%; 7h R= p-Cl, R1,R2=
, 48%;
, 55%
, 64%;
Scheme 1 Reagents and conditions: (i) SOCl2, 80°C, 24 h; (ii) 2-amino-6-bromopyridine 11,
CH3CN, pyridine, RT, 4 h; (iii) 5 mol% Cu(I)I, 2 eq. HO(CH2)2OH, R1R2NH, K3PO4,
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dioxane, 125°C, 24 h; (iv) 2 mol% Pd2(dba)3, 6 mol% (rac)-BINAP, R1R2NH, KOtBu,
dioxane, 120 - 135°C, 24 h. aYields of copper-catalysed reactions are shown in parentheses.
A comparison of the yields obtained for the three reactions where Cu-catalysed and Pd-
catalysed reactions were performed shows that the Pd-catalysed reactions gave considerably
higher yields for benzylamine and aniline nucleophiles, while very similar yields were
obtained for the cyclohexylamine reactions (Scheme 1). Buchwald et al. found that in many
instances Cu and Pd mediated C-N cross-coupling reactions are complementary, with Pd
catalysis favouring reactions with aniline as nucleophile and Cu catalysis favouring reaction
of aliphatic amines.21 To prove the particular utility of rac-BINAP as a ligand in our
reactions, we tested triphenylphosphine as supporting ligand and only isolated starting
material from these reactions. One of the problems with using heteroaryl halides, such as our
bromopyridine substrate, is that they are also capable of coordination to palladium and
displacement of the phosphine ligand can occur, which leads to deactivation of the catalyst.22
The use of monodentate (Ph3P) versus bidentate (BINAP) phosphine ligands may change the
rate of reaction,23 and this may have an influence on reaction outcome. We performed a
single reaction testing an alternative bidentate ligand, Xantphos, in the preparation of
compound 7e and this reaction was successful. We also tested both Cu and Pd-catalysed
reactions under microwave irradiation conditions but achieved inferior yields in comparison
to those obtained by conventional heating.
Of crucial importance to the success of our Pd-catalysed reactions was allowing sufficient
time – about 5 minutes – for pre-mixing of the pre-catalyst and supporting ligand at 80°C
under nitrogen purge prior to successive addition of the heteroaryl halide, nucleophile and
base. Where this protocol was not followed, mostly starting material was recovered from the
reactions. One possible explanation for this could be that since these cross-coupling reactions
utilise very low catalyst loadings, it is important to attain sufficient homogeneity of the active
catalyst species prior to the addition of other reagents. The point made previously about the
possible coordination of the pyridine substrate to palladium could also be a factor, if
coordination between the supporting ligand and pre-catalyst is not concluded prior to the
addition of the substrate.
The more flexible scaffold 8 was accessed through the reductive amination of benzaldehyde
derivative 13 with 2-amino-6-bromopyridine 11 under mild acid catalysis in the presence of
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sodium cyanoborohydride to afford 14a, as shown in Scheme 2. Pd-catalysed cross-coupling
reactions with a variety of N-nucleophiles were successful after Boc-protection of the
benzylamine nitrogen to give 14b. Subsequent to cross-coupling, Boc-deprotection gave rise
to the desired compounds 8a-e in reasonable overall yields (Scheme 2). Cross-coupling
reactions carried out without Boc protection led to selectivity problems, with the benzylamine
nitrogen competing with the added nucleophile for bromide displacement and leading to a
mixture of products. Cross-coupling reactions of Boc-protected intermediate 14b could be
achieved using the milder base Cs2CO3. An alternative approach to scaffold 8 by direct
reduction of scaffold 7 was tested by attempted LiAlH4 reduction of 7d in dry refluxing THF
or toluene for 24h, but amide reduction proved unsuccessful as only the starting material was
recovered.
Cl
O
Cl
Cl
R1
iii, iv
i
H
N
R
N
Br
N
N
N
R2
+
H
H2N
N
Br
13
11
14a R=H
8
ii
14b R=Boc
8a R1= c-hex, R2= H, 60%b; 8b R1= CH2Ph, R2= H, 57%b;
8c R1= Ph, R2=H, 51%b; 8d R1,R2= , 63%b;
8e R1,R2=
, 44%b
Scheme 2 Reagents and conditions: (i) NaCNBH3, 4Å MS, MeOH, reflux, pH 5-6; (ii)
(Boc)2O, 0.1 - 0.2 equiv. DMAP, CH3CN; (iii) 2 mol% Pd2(dba)3, 6 mol% (rac)-BINAP,
b
R1R2NH, Cs2CO3, dioxane, 120°C, 24 h; (iv) aq. HCl, CHCl3, reflux, 2 h. These yields
include Boc-protection, cross-coupling and deprotection steps.
The sulfonamide scaffold 9 was prepared by reaction of the aryl sulfonyl chloride 15 with 2-
amino-6-bromopyridine (11) as shown in Scheme 3. Once again, Pd-catalysed cross-coupling
reactions with N-nucleophiles gave rise to the desired products (9a-h).
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9a R= o-Cl, R1= c-hex, R2= H, 63%; 9b R= o-Cl, R1= CH2Ph, R2= H, 50%;
9c R= o-Cl, R1= Ph, R2=H, 58%; 9d R= o-Cl, R1,R2=
, 79%;
9f R= H, R1= c-hex, R2= H, 65%;
, 56%; 9h R= H, R1,R2= , 61%b
9e R= o-Cl, R1,R2=
9g R= H, R1,R2=
, 57%;
Scheme 3 Reagents and conditions: (i) CH3CN, pyridine, reflux, 24 h; (ii) 2 mol%
Pd2(dba)3, 6 mol% (rac)-BINAP, R1R2NH, KOtBu, dioxane, 120 - 130°C, 24 h.
Pleasingly, similar reaction conditions to those shown in Schemes 1-3 for nitrogen
nucleophiles proved to be applicable to oxygen- and sulfur-nucleophiles and these were
successfully used in palladium cross-coupling reactions to prepare scaffolds 17-19 (Fig. 4). In
contrast to compounds 18a-c, compounds 18d and 18e could be successfully prepared
without Boc protection of the benzylamine nitrogen. In general, oxygen nucleophiles required
slightly higher temperatures (140°C) than the corresponding nitrogen or sulfur nucleophiles
but no material differences in reaction yield were observed. For example in the benzamide
series, aniline (65%), phenol (70%) and thiophenol (63%) gave comparable results.
17a X= O, R1= n-butyl, 45%; 18a X= O, R1= n-butyl, 53%; 19a X= O, R= o-Cl, R1= n-butyl, 59%;
17b X= O, R1= Ph, 70%;
18b X= O, R1= Ph, 65%;
19b X= O, R= o-Cl, R1= CH2Ph, 80%;
17c X= O, R1= CH2Ph, 52%; 18c X= O, R1= CH2Ph, 61%; 19c X= S, R= o-Cl, R1= Ph, 83%;
17d X= S, R1= Ph, 63%;
18d X= S, R1= Ph, 63%;
19d X= S, R= o-Cl, R1= CH2Ph, 88%;
17e X= S, R1= CH2Ph, 52%;
18e X= S, R1= CH2Ph, 65%; 19e X= O, R= H, R1= n-butyl, 53%;
19f X= O, R= H, R1= CH2Ph, 64%
Fig. 4
Of particular interest was one of the attempted cross-coupling reactions that did not give the
anticipated product. Attempted displacement of the bromine in compound 20 by piperidine
under palladium cross-coupling conditions gave product 21 in high yield (Scheme 4). No
product corresponding to bromine displacement by piperidine was isolated. In order to
investigate the reaction conditions required for displacement of fluorine by piperidine, the
reaction was repeated without palladium catalyst. The reaction proceeded in even better yield
in the absence of catalyst, showing that this facile nucleophilic aromatic substitution must be
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promoted by the presence of the electron withdrawing ortho-amide functionality only.
Another repetition of the reaction in the absence of strong base (KOtBu or KHMDS) was also
successful; showing that piperidine itself was able to fulfil this function. We subsequently
subjected compound 21 to Pd-catalysed cross-coupling with piperidine and obtained the
expected product 22, where displacement of bromine had occurred. This complete selectivity
for nucleophilic aromatic substitution at fluorine, even in the presence of bromine, followed
by the possibility of subsequently displacing bromine with a nucleophile makes compound 20
a versatile intermediate for the preparation of more complex scaffolds. Preliminary results
obtained using benzyl alcohol as the nucleophile in a palladium-catalysed reaction with 20
also yielded only the product resulting from displacement of fluorine. A change in solvent
from dioxane to DMF was necessary as a result of precipitation of material during the course
of the reaction. Thus indications are that this nucleophilic aromatic substitution reaction may
prove general to a whole range of nucleophiles, and this is currently the subject of further
investigation.
Scheme 4 Reagents and conditions: (i) 2 mol% Pd2(dba)3, 6 mol% (rac)-BINAP, piperidine,
2 eq. KOtBu, dioxane, reflux, 125°C, 24 h, 85% yield; (ii) 2 eq. KOtBu or KHMDS, dioxane,
100°C, 2 h, 99% yield; (iii) 2 mol% Pd2(dba)3, 6 mol% (rac)-BINAP, piperidine, 2 eq.
KOtBu, dioxane, reflux, 125°C, 24 h, 85% yield.
Synthesised compounds were subjected to antiviral and antimicrobial assays, 24 with N-
substituted benzamide derivative 7e showing significant antiviral activity (0.7 ꢀM) against
wild-type HIV-1 using an in vitro single-cycle assay. This compound, together with
benzamide derivative 12e, demonstrated noteworthy antimicrobial (39 ꢀg.ml-1) activity
against S. aureus. As a class, N-substituted pyridyl-benzamides have not previously been
known for anti-HIV activity.
3. Conclusion
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A Pd-catalysed cross coupling approach was successfully applied to the synthesis of three
small compound libraries of novel pyridyl-benzamides, pyridyl-benzylamines and pyridyl-
sulfonamides. The synthetic approach using Pd2(dba)3 as palladium source and rac-BINAP as
supporting ligand proved versatile over all compound classes and for N-, O- and S-
nucleophiles.
4. Experimental section
4.1. General
All solvents and amines were freshly distilled prior to use. Other reagents were used as
purchased from Sigma-Aldrich. All infrared spectra were recorded neat using a Bruker
TENSOR 27 single channel infrared spectrometer. All melting points are uncorrected and
1
were performed using open capillary tubes on a Stuart SMP 10 melting point apparatus. H
13
and C NMR spectra were recorded using either a Bruker AVANCE 111 300 or 500 MHz
spectrometer in deuterated chloroform (CDCl3) with trimethylsilane (TMS) as internal
standard (δ= 0) for 1H NMR, and CDCl3 (δ= 77.0 ppm) for 13C NMR. The chemical shift (δ)
is reported in ppm and the coupling constants (J) in Hz. High resolution mass spectral data
was collected on a Waters Synapt G2 using an ESI positive source and a cone voltage of 15
79
V. The exact masses of bromine- and chlorine-containing compounds are based on the Br
isotope and 35Cl isotope, respectively. TLC was performed on aluminium-backed Merck
silica gel 60 F254 plates. The purification of compounds by column chromatography was
performed using gravity (particle size 0.063-0.200 mm) or flash (particle size 0.040-0.063
mm) silica gel 60 purchased from Merck.
4.2. General procedure for the preparation of compounds 12a-e
To an appropriately substituted benzoic acid (10.0 mmol) in a round-bottomed flask was
added excess thionyl chloride (15 ml). The mixture was gently stirred and refluxed at 80°C in
an oil bath for 24 h. After cooling the reaction mixture to room temperature, excess thionyl
chloride was evaporated leaving a pale yellow benzoyl chloride residue which was dissolved
in distilled acetonitrile (5 ml) and cautiously added to an ice-cold mixture of 2-amino-6-
bromo-pyridine (1.6 g, 9.2 mmol) and pyridine (3 ml) in acetonitrile (15 ml). The mixture
was stirred at 0°C for 30 min, warmed to room temperature and stirred for 4 h. Solvent was
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removed under reduced pressure and the residue was dissolved in dichloromethane (20 ml)
and washed successively with aqueous saturated NaHCO3 (2 x 10 ml), saturated brine
solution (10 ml) and distilled water (2 x 10 ml) and then dried over anhydrous MgSO4 or
Na2SO4.The solvent was removed in vacuo and the crude mixture purified by flash silica gel
column chromatography, eluting with 3 – 5% EtOAc/hexane to give the desired product.
4.2.1. N-(6-bromopyridin-2-yl)-2-chlorobenzamide (12a)
Product 12a (267 mg, 86%) was isolated as a white crystalline product. Mp: 103 - 104°C; IR
1
(cm-1): 3177 (NH), 1683 (C=O), 1592 (C=N), 1564 (NH bend), 1428 (C=C); H NMR (300
MHz, CDCl3) δ 8.58 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.74 – 7.67 (m, 1H), 7.63 (t, J = 8.0
Hz, 1H), 7.50 – 7.34 (m, 3H), 7.27 (d, J = 7.5 Hz, 1H, partly obscured by CDCl3); 13C NMR
(75 MHz, CDCl3) δ 164.8, 151.1, 140.7, 139.4, 134.4, 132.2, 130.9, 130.6, 129.9, 127.3,
124.1, 112.6; HRMS (ES+) Calculated for C12H9BrClN2O [M+H]+: 310.9587, found:
310.9576.
4.2.2. N-(6-bromopyridin-2-yl)benzamide (12b)
Product 12b (254 mg, 92%) was isolated as a white solid. Mp: 86 - 87°C; IR (cm-1): 3254
(NH str.), 3083 (CH str.), 1658 (C=O str.), 1581 (C=N str.), 1558 (NH bend), 1423 (C=C); 1H
NMR (500 MHz, CDCl3) δ 8.61 (br s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 7.92 – 7.88 (m, 2H),
7.63 – 7.55 (m, 2H), 7.50 (t, J = 8.4 Hz, 2H), 7.24 (d, J = 7.7 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 165.6, 151.6, 140.7, 139.3, 133.7, 132.5, 128.9, 127.2, 123.7, 112.5; HRMS (ES+)
Calculated for C12H10BrN2O [M+H]+: 276.9977, found: 276.9974.
4.2.3. N-(6-bromopyridin-2-yl)-3-chlorobenzamide (12c)
Product 12c (295 mg, 95%) was isolated as white crystals. Mp: 119 - 120°C; IR (cm-1): 3278
(NH str.), 1669 (C=O), 1600 (C=N str.), 1561 (NH bend), 1431 (C=C); 1H NMR (500 MHz,
CDCl3) δ 8.69 (s, 1H), 8.31 (d, J = 8.1, 1H), 7.88 (t, J = 1.9 Hz, 1H) 7.75 (dt, J = 7.8, 1.3 Hz,
1H), 7.59 (t, J = 7.9 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 7.6
13
Hz, 1H); C NMR (125 MHz, CDCl3) δ 164.3, 151.3, 140.7, 139.3, 135.4, 135.1, 132.5,
130.1, 127.7, 125.2, 124.0, 112.6; HRMS (ES+) Calculated for C12H9BrClN2O [M+H]+:
310.9587, found: 310.9582.
4.2.4. N-(6-bromopyridin-2-yl)-4-chlorobenzamide (12d)
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Product 12d (304 mg, 98%) was isolated as white crystals. Mp: 128 - 129°C; IR (cm-1): 3277
(NH str.), 1669 (C=O), 1589 (C=N str.), 1561 (NH bend), 1430 (C=C); 1H NMR (300 MHz,
CDCl3) δ 8.55 (s, 1H), 8.32 (dt, J = 8.2, 0.6 Hz, 1H), 7.91 – 7.80 (m, 2H), 7.61 (t, J = 7.8 Hz,
1H), 7.51 – 7.44 (m, 2H), 7.26 (dt, J = 8.2, 0.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 164.5,
151.4, 140.7, 139.4, 139.0, 132.1, 129.2, 128.7, 123.9, 112.5; HRMS (ES+) Calculated for
C12H9BrClN2O [M+H]+: 310.9587, found: 310.9584.
4.2.5. N-(6-bromopyridin-2-yl)-4-cyanobenzamide (12e)
Product 12d (283 mg, 94%) was isolated as white crystals. Mp: 197 - 198°C; IR (cm-1): 3436
and 3303 (NH str.), 2237 (CN str.), 1685 (C=O), 1584 (C=N str.), 1569 (NH bend), 1434
(C=C); 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.10 – 7.96 (m,
13
2H), 7.89 – 7.77 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.30 (dd, J = 7.8, 0.7 Hz, 1H); C NMR
(75 MHz, CDCl3) δ 163.7, 151.0, 140.9, 139.5, 137.5, 132.8, 127.9, 124.4, 117.7, 116.2,
112.6; HRMS (ES+) Calculated for C13H9BrN3O [M+H]+: 301.9929, found: 301.9927.
4.3. General Procedure for Copper (1) Iodide - catalyzed cross-coupling reaction –
Method 1 to prepare compounds 7a-c
Copper (I) iodide (9.5 – 29 mg; 5 - 15mol %), N-(6-bromopyridin-2-yl)-2-chlorobenzamide
12a (311 mg, 1.0 mmol), dioxane (3 ml, degassed) and a magnetic stirrer were added to an
oven-dried 10ml round bottomed flask containing dioxane (3 ml) under nitrogen purge. The
flask was sealed and heated with stirring at 80°C in an oil bath (5 min). Ethylene glycol (2
eq.), amine (1.3 mmol) and K3PO4 (510 mg, 2.4 mmol) were added and the sealed reaction
was heated at 120°C -135°C for 24 h. The reaction mixture was cooled to room temperature,
diluted with chloroform/dichloromethane (15 ml) and filtered through celite. The filtrate was
washed successively with saturated aqueous NaHCO3 (10 ml) and distilled water (2 x10 ml).
After drying over MgSO4, the solvent was removed under reduced pressure and the crude
brown mixture was purified by silica gel column chromatography, eluting the desired
compound with 2 – 5% EtOAc/hexane.
4.4. General Procedure for Palladium/BINAP-catalyzed cross-coupling reaction –
Method 2 to prepare compounds 7a-i
Tris-(dibenzylideneacetone)-di-palladium (0) [Pd2dba3], (19 mg, 2 mol %), rac-BINAP (38
mg, 6 mol %), dioxane (3 – 5 ml, degassed) and a magnetic stirrer were added to an oven-
dried 10 ml round bottomed flask and purged with nitrogen. The flask was sealed and heated
12

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with stirring at 80°C in an oil bath (5 min). An N-(6-bromopyridin-2-yl)benzamide 12a-e (1.0
mmol), an amine (1.3 – 3.0 mmol) and potassium tert-butoxide (2.4 mmol) were added and
the sealed reaction was heated at 120 - 130°C for 24 h. The reaction mixture was cooled to
room temperature, diluted with chloroform (15 ml) and filtered. The filtrate was washed
successively with saturated aqueous NaHCO3 (10 ml) and distilled water (2x10 ml). After
drying over MgSO4, the solvent was removed in vacuo and the crude brown mixture was
purified by silica gel flash column chromatography, eluting the title compound with 2 – 5%
EtOAc/hexane.
4.4.1. 2-Chloro-N-(6-(cyclohexylamino)-pyridin-2-yl)-benzamide (7a)
Reaction of N-(6-bromopyridin-2-yl)-2-chlorobenzamide 12a (311 mg, 1.0 mmol) with
freshly distilled cyclohexylamine (129 mg, 1.3 eq.) using method 1 gave rise to product 7a
(261 mg, 79%) as a golden yellow oil. Use of method 2 also gave rise to product 7a (247 mg,
75%); IR (cm-1) 3388 (NH str.), 2927 and 2852 (CH str.), 1681 (C=O), 1611 (C=N), 1430
(C=C); 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.66 (dd, J = 7.4, 1.6 Hz, 1H), 7.56 (d, J
= 7.7 Hz, 1H), 7.51 – 7.29 (m, 3H), 6.15 (d, J = 8.1 Hz, 1H), 4.35 (d, J = 6.9 Hz, 1H ), 3.60 –
13
3.33 (m, 1H), 2.18 – 1.92 (m, 2H), 1.81 – 1.56 (m, 3H), 1.45 – 0.78 (m, 6H); C NMR (75
MHz, CDCl3) δ 164.5, 157.0, 149.6, 139.7, 135.4, 131.5, 130.9, 130.4, 129.8, 127.1, 103.2,
102.0, 50.2, 33.3, 25.8, 24.9; HRMS (ES+) Calculated for C18H21ClN3O [M+H]+: 330.1373,
found: 330.1374.
4.4.2 N-(6-(benzylamino)-pyridin-2-yl)-2-chlorobenzamide (7b)
Reaction of N-(6-bromopyridin-2-yl)-2-chlorobenzamide 12a (311 mg, 1.0 mmol) with
freshly distilled benzylamine (139.19 mg, 1.3 eq.) using method 1 gave product 7b (85 mg,
25%) as a pale yellow oil. Use of method 2 also gave 7b (209 mg, 62%). IR (cm-1) 3379 (NH
1
str.), 3028 (CH str.), 1670 (C=O), 1608 (C=N), 1432 (C=C); H NMR (300 MHz, CDCl3) δ
8.29 (s, 1H), 7.68 (dd, J = 7.1, 2.0 Hz, 1H), 7.63 (d, J = 7.0 Hz, 1H), 7.50 – 7.26 (m, 9H),
13
6.18 (d, J = 8.1 Hz, 1H), 4.76 (t, J = 5.8 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H); C NMR (75
MHz, CDCl3) δ 164.5, 157.4, 149.5, 139.8, 139.2, 135.3, 131.6, 130.9, 130.4, 129.9, 128.6,
127.4, 127.3, 127.1, 103.4, 102.7, 46.1; HRMS (ES+) Calculated for C19H17ClN3O [M+H]+:
338.1060, found: 338.1064.
4.4.3. 2-Chloro-N-(6-(phenylamino)-pyridin-2-yl)benzamide (7c)
13

ACCEPTED MANUSCRIPT
Reaction of N-(6-bromopyridin-2-yl)-2-chlorobenzamide 12a (311 mg, 1.0 mmol) with
freshly distilled aniline (121 mg, 1.3 eq.) using method 1 gave product 7c (139 mg, 43%) as a
pale yellow oil. Use of method 2 also gave 7c (210 mg, 65%); IR (cm-1) 3301 (NH str.),
1
3043 (CH str.), 1654 (C=O), 1590 (C=N), 1561 (NH bend), 1494 (C=C); H NMR (300
MHz, CDCl3) δ 9.30 (s, 1H), 8.56 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.63 – 7.54 (m, 2H), 7.39
– 7.26 (m, 4H), 7.25 -7.20 (m, 3H), 7.05 (t, J = 7.3, 1H), 6.80 (ddd, J = 8.0, 6.0, 2.3 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 167.7, 151.6, 146.7, 141.0, 140.5, 139.4, 133.4, 129.4, 127.7,
123.6, 123.2, 121.7, 118.0, 116.5, 115.7, 112.4; HRMS (ES+) Calculated for C18H15ClN3O
[M+H]+: 324.0904, found: 324.0893.
4.4.4. 2-Chloro-N-(6-morpholinopyridin-2-yl)benzamide (7d)
Reaction of N-(6-bromopyridin-2-yl)-2-chlorobenzamide 12a (311 mg, 1.0 mmol) with
freshly distilled morpholine (113.19 mg, 1.3 eq.) using method 2 gave product 7d (178 mg,
56%) as a pale yellow oil. IR (cm-1): 3396 and 3251 (NH str.), 2962 and 2852 (CH str.), 1676
1
(C=O), 1600 (C=N), 1566 (NH bend), 1436 (C=C); H NMR (300 MHz, CDCl3) δ 8.37 (s,
1H), 7.76 – 7.63 (m, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.47 – 7.28 (m, 3H), 6.39 (d, J = 6.6 Hz,
13
1H), 3.85 – 3.71 (m, 4H), 3.52 – 3.33 (m, 4H); C NMR (75 MHz, CDCl3) δ 164.6, 158.3,
149.4, 140.0, 135.4, 131.6, 130.8, 130.4, 129.8, 127.1, 103.3, 103.1, 66.7, 45.4; HRMS (ES+)
Calculated for C16H17ClN3O2 [M+H]+: 318.1009, found: 318.1006.
4.4.5. 2-Chloro-N-(6-(piperidin-1-yl)-pyridin-2-yl)benzamide (7e)
Reaction of N-(6-bromopyridin-2-yl)-2-chlorobenzamide 12a (311 mg, 1.0 mmol) with
freshly distilled piperidine (111 mg, 1.3 eq.) using method 2 gave compound 7e (214 mg,
68%) as a light yellow oil which solidified on drying. Mp: 111 - 113°C. IR (cm-1) 3190 (NH
1
str.), 2929 and 2851 (CH str.), 1683 (C=O), 1605 (C=N), 1561 (NH bend), 1440 (C=C); H
NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.70 – 7.42 (m, 3H), 7.41 – 7.28 (m, 2H), 7.28 –
13
7.17 (m, 1H), 6.33 (d, J = 8.3 Hz, 1H), 3.54 – 3.27 (m, 4H), 1.67 – 1.45 (m, 6H); C NMR
(75 MHz, CDCl3) δ 164.8, 158.2, 149.5, 139.8, 135.6, 131.2, 130.8, 130.2, 129.4, 127.0,
103.2, 101.8, 46.0, 25.4, 24.7; HRMS (ES+) Calculated for C17H19ClN3O [M+H]+: 316.1217,
found: 316.1206.
4.4.6. N-(6-(piperidin-1-yl)-pyridin-2-yl)benzamide (7f)
Reaction of N-(6-bromopyridin-2-yl)benzamide 12b (278 mg, 1.0 mmol) with piperidine
(255 mg, 3.0 eq.) using method 2 gave compound 7f (155 mg, 55%) as a pale brown oil. IR
14

ACCEPTED MANUSCRIPT
1
(cm-1) 3290 (NH str.), 2931 and 2852 (CH str.), 1670 (C=O), 1604 (C=N), 1440 (C=C); H
NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 7.96 – 7.85 (m, 2H), 7.66 – 7.44 (m, 5H), 6.42 (d, J
13
= 8.2 Hz, 1H), 3.57 – 3.42 (m, 4H), 1.69 – 1.60 (m, 6H); C NMR (75 MHz, CDCl3) δ
165.4, 158.4, 149.7, 139.8, 134.9, 131.9, 128.7, 127.1, 103.0, 101.9, 46.2, 25.5, 24.8; HRMS
(ES+) Calculated for C17H20N3O [M+H]+: 282.1606, found: 282.1603.
4.4.7. 3-Chloro-N-(6-(piperidin-1-yl)-pyridin-2-yl)benzamide (7g)
Reaction of N-(6-bromopyridin-2-yl)-3-chlorobenzamide 12c (311 mg, 1.0 mmol) with
piperidine (255 mg, 3.0 eq.) using method 2 gave product 7g (164 mg, 52%) as a pale yellow
oil which solidified on drying. Mp: 94 - 96°C; IR (cm-1) 3289 (NH str.), 2928 and 2849 (CH
1
str.), 1655 (C=O), 1604 (C=N), 1440 (C=C); H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H),
7.91 – 7.86 (m, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.58 – 7.48 (m, 3H), 7.40 (t, J = 7.9 Hz, 1H),
13
6.42 (d, J = 8.1 Hz, 1H), 3.53 – 3.46 (m, 4H), 1.67 – 1.57 (m, 6H); C NMR (125 MHz,
CDCl3) δ 164.0, 158.4, 149.4, 139.8, 136.7, 134.9, 131.9, 130.0, 127.5, 125.2, 103.3, 101.8,
46.2, 25.5, 24.7; HRMS (ES+) Calculated for C17H19ClN3O [M+H]+: 316.1217, found:
316.1206.
4.4.8. 4-Chloro-N-(6-(piperidin-1-yl)-pyridin-2-yl)benzamide (7h)
Reaction of N-(6-bromopyridin-2-yl)-4-chlorobenzamide 12d (311 mg, 1.0 mmol) with
piperidine (255 mg, 3.0 eq.) using method 2 gave product 7h (202 mg, 64%) as off-white
crystals. Mp: 140 - 142°C; IR (cm-1) 3273 (NH str.), 2932 and 2845 (CH str.), 1658 (C=O),
1
1603 (C=N), 1425 (C=C); H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.85 – 7.77 (m, 2H),
7.62 – 7.48 (m, 2H), 7.48 – 7.39 (m, 2H), 6.42 (d, J = 7.9 Hz, 1H), 3.55 – 3.43 (m, 4H), 1.67
13
– 1.56 (m, 6H); C NMR (125 MHz, CDCl3) δ 164.4, 158.4, 149.5, 139.8, 138.1, 133.2,
128.9, 128.6, 103.2, 101.9, 46.2, 25.5, 24.7; HRMS (ES+) Calculated for C17H19ClN3O
[M+H]+: 316.1217, found: 316.1205.
4.4.9. 4-Cyano-N-(6-(piperidin-1-yl)-pyridin-2-yl)benzamide (7i)
Reaction of N-(6-bromopyridin-2-yl)-4-cyanobenzamide 12e (319 mg, 1.0 mmol) with
piperidine (255 mg, 3.0 eq.) using method 2 gave product 7i (149 mg, 48%) as pale yellow
crystals. Mp: 127 - 128°C; IR (cm-1): 3344 (NH str.), 2934 and 2855 (CH str.), 2230 (CN),
1667 (C=O), 1601 (C=N), 1443 (C=C); 1H NMR (300 MHz, CDCl3) δ 8.20 (br s, 1H), 8.02 –
7.97 (m, 2H), 7.83 – 7.74 (m, 2H), 7.58 – 7.49 (m, 2H), 6.45 (dd, J = 6.2, 2.8 Hz, 1H), 3.52 –
3.46 (m, 4H), 1.68 – 1.58 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 163.5, 158.4, 149.1, 139.9,
15

ACCEPTED MANUSCRIPT
138.8, 132.6, 127.8, 117.9, 115.5, 103.6, 101.8, 46.1, 25.5, 24.7; HRMS (ES+) Calculated for
C18H19N4O [M+H]+: 307.1559, found: 307.1554.
4.4.10. 6-Bromo-N-(2-chlorobenzyl)pyridin-2-amine (14a)
2-Chlorobenzaldehyde 13 (1.47 g, 10 mmol), 2-amino-6-bromo-pyridine 11 (1.55 g, 9.0
mmol) and 4Å molecular sieves were placed into a 100 ml round bottomed flask containing
dry acetonitrile (25 ml). The pH was adjusted to pH 5 – 6 by dropwise addition of conc. HCl,
with bromocresol green as indicator. The reaction mixture was stirred under reflux until the
reactants were quantitatively converted to the imine intermediate. Sodium cyanoborohydride
(0.9 g, 15.0 mmol) was added portion-wise over 2 h while maintaining the pH of the reaction
mixture between 5 and 6. After 24 h, the reaction mixture was cooled, filtered and the solvent
removed under reduced pressure to leave an off-white residue which was purified by silica
gel column chromatography, eluting with 5 – 10% EtOAc/hexane, to give 14a (2.35 g, 88%)
as off-white crystals. Mp: 77 - 78°C; IR (cm-1): 3261 (NH str.), 3085 (CH str.), 1600 and
1
1590 (C=N str.), 1560 (NH bend), 1427 (C=C); H NMR (300 MHz, CDCl3) δ 7.48 – 7.34
(m, 2H), 7.29 – 7.16 (m, 3H), 6.74 (dd, J = 7.4, 0.6 Hz, 1H), 6.25 (d, J = 8.1 Hz, 1H), 5.28 –
13
5.14 (m, 1H), 4.57 (d, J = 6.2 Hz, 2H); C NMR (75 MHz, CDCl3) δ 158.5, 140.3, 139.6,
135.8, 133.5, 129.6, 129.4, 128.7, 127.0, 116.4, 104.7, 44.0. HRMS (ES+) Calculated for
C12H11BrClN2 [M+H]+: 296.9794, found: 296.9792.
4.4.11. tert-Butyl (6-bromopyridin-2-yl)(2-chlorobenzyl)carbamate (14b)
Dimethylaminopyridine (DMAP, 0.2 g, 1.6 mmol) and di-tert-butyl dicarbonate (3.27 g, 15.0
mmol) were added to a 50 ml round bottomed flask containing 6-bromo-N-(2-chlorobenzyl)-
pyridin-2-amine 14a (2.96 g, 10.0 mmol) dissolved in dry acetonitrile (20 ml). The reaction
mixture was stirred slowly at room temperature (5 min) before heating the mixture at 40°C
for 24 h. After cooling to room temperature, the solvent was removed under reduced pressure
and the crude mixture was dissolved in dichloromethane (20 ml), washed twice with distilled
water (2 x 15 ml) and dried over anhydrous MgSO4. The organic solvent was removed in
vacuo to leave a pale yellow crude product which was purified by silica gel column
chromatography, eluting with 10% EtOAc/hexane to give 14b (4.19 g, 98%) as an off-white
oily product which solidified on drying. 1H NMR (CDCl3, 500 MHz) δ 7.80 ( d, J = 8.2 Hz,
1H), 7.50 – 7.45 ( m, 1H), 7.35 – 7.32 (m, 1H), 7.22 – 7.18 (m, 1H ), 7.17 – 7.13 (m, 3H ),
13
5.28 (s, 2H), 1.38 (s, 9H); C NMR (125 MHz, CDCl3) δ 154.2, 153.6, 139.2, 138.9, 136.5,
16

ACCEPTED MANUSCRIPT
132.7, 129.2, 128.0, 127.9, 126.6, 123.2, 117.3, 82.1, 47.7, 28.0; HRMS (ES+) Calculated for
C17H20ClN2O2 [M+H]+: 319.1213, found: 319.1221.
4.5. General procedure for the preparation of compounds 8a-e
Tris-(dibenzylideneacetone)-di-palladium (0) [Pd2dba3], (19 mg, 2mol %), rac-BINAP (38
mg, 6 mol %), dioxane (3 – 5 ml, degassed) and a magnetic stirrer were added to an oven-
dried 10 ml round bottomed flask under nitrogen purge. The flask was sealed and heated with
stirring at 80°C in an oil bath for 5 min. tert-Butyl (6-bromopyridin-2-yl)(2-
chlorobenzyl)carbamate 14b (420 mg, 1mmol), an amine (1.3 – 3.0eq.) and cesium carbonate
(782 mg, 2.4 mmol) were added and the sealed reaction was heated at 120°C for 24 h. The
reaction mixture was cooled to room temperature, diluted with dichloromethane/chloroform
(15 ml) and filtered. The filtrate was washed successively with saturated aqueous NaHCO3
(10 ml) and distilled water (2 x 10 ml). After drying over anhydrous Na2SO4, the solvent was
removed under reduced pressure and the crude mixture was purified by silica gel flash
column chromatography, eluting the desired Boc-protected compound with 2 – 5%
EtOAc/hexane. The Boc-protected compound was dissolved in chloroform (10 ml)
containing hydrochloric acid (3 ml) and warmed at 30°C for 2 h. The mixture was cautiously
neutralised with sodium bicarbonate, washed with distilled water (2 x 10 ml) and dried over
anhydrous Na2SO4. The solvent was removed in vacuo to give the desired compounds 8a-e.
4.5.1. N2-(2-chlorobenzyl)-N6-cyclohexylaminopyridine-2,6-diamine (8a)
Reaction of 14b with cyclohexylamine (129 mg, 1.5 eq.) gave compound 8a (189 mg, 60%)
as a pale yellow oil. IR (cm-1) 3417 (NH str.), 2926 and 2851 (CH str.), 1588 and 1570 (NH
bend), 1420 (C=C); 1H NMR (300 MHz, CDCl3) δ 7.81 – 7.71 (m, 1H), 7.44 – 7.30 (m, 4H),
7.28 – 7.20 (m, 2H), 5.80 (d, J = 8.5 Hz, 1H), 5.58 (d, J = 8.3 Hz, 1H), 4.51 (d, J = 5.9 Hz,
2H), 3.33 – 3.19 (m, 1H), 2.03 – 1.92 (m, 2H), 1.86 – 1.73 (m, 2H), 1.67 – 1.58 (m, 1H), 1.43
– 1.22 (m, 5H);13C NMR (75 MHz, CDCl3) δ 152.3, 151.6, 145.0, 134.0, 132.8, 129.7, 128.9,
128.0, 127.2, 93.7, 92.0, 51.5, 43.7, 32.3, 25.2, 24.6. HRMS (ES+) Calculated for C18H23ClN3
[M+H]+: 316.1581, found: 316.1599.
4.5.2. N2-benzyl-N6-(2-chlorobenzyl)-pyridine-2,6-diamine (8b)
Reaction of 14b with benzylamine (161 mg, 1.5 eq.) gave compound 8b (184 mg, 57%) as a
pale yellow oil. IR (cm-1) 3417 (NH str.), 2926 and 2851 (CH str.), 1588 and 1570 (NH
bend), 1420 (C=C); 1H NMR (300 MHz, CDCl3) δ 7.44 – 7.13 (m, 10H), 5.73 (d, J = 6.0 Hz,
17

ACCEPTED MANUSCRIPT
1H), 5.70 (d, J = 6.0 Hz, 1H), 4.82 – 4.70 (m, 1H), 4.69 – 4.59 (m, 1H), 4.53 (d, J = 6.2 Hz,
13
2H), 4.43 (d, J = 5.8 Hz, 2H); C NMR (75 MHz, CDCl3) δ 158.0, 157.8, 139.8, 139.1,
137.2, 133.2, 129.4, 129.2, 128.5, 128.2, 127.4, 127.0, 126.8, 95.4, 95.3, 46.3, 43.9. HRMS
(ES+) Calculated for C19H19ClN3 [M+H]+: 324.1268, found: 324.1267.
4.5.3. N2-(2-chlorobenzyl)-N6-phenylpyridine-2,6-diamine (8c)
Reaction of 14b with aniline (140 mg 1.5 eq.,) gave compound 8c (158 mg, 51%) as a pale
brown oil. IR (cm-1) 3400 (NH str.), 2958 and 2920 (CH str.), 1578 (NH bend), 1432 (C=C);
1H NMR (300 MHz, CDCl3) δ 7.48 – 7.13 (m, 9H), 7.02 – 6.92 (m, 1H), 6.32 (s, 1H), 6.16
(d, J = 7.9 Hz, 1H), 5.85 (d, J = 7.9, 1H), 4.92 – 4.79 (m, 1H), 4.58 (d, J = 6.2 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 157.8, 154.9, 140.9, 139.2, 137.0, 133.3, 129.4, 129.0, 128.3,
126.9, 122.0, 119.9, 97.4, 97.2, 43.9. HRMS (ES+) Calculated for C18H17ClN3 [M+H]+:
310.1111, found: 310.1109.
4.5.4. N-(2-chlorobenzyl)-6-morpholinopyridine-2-amine (8d)
Reaction of 14b with morpholine (131 mg, 1.5 eq.) gave compound 8d (133 mg, 44%) as a
pale brown oil. IR (cm-1) 3369 (NH str.), 2959 and 2852 (CH str.), 1581 (NH bend), 1433
(C=C); 1H NMR (300 MHz, CDCl3) δ 7.48 – 7.31 (m, 2H), 7.29 – 7.13 (m, 3H), 5.93 (d, J =
8.4 Hz, 1H), 5.79 (d, J = 8.4 Hz, 1H) 4.79 (br s, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.89 – 3.72 (m,
13
4H), 3.55 – 3.35 (m, 4H); C NMR (75 MHz, CDCl3) δ 158.8, 157.3, 139.1, 137.2, 133.2,
129.4, 129.2, 128.2, 126.8, 96.4, 95.5, 66.8, 45.7, 43.8. HRMS (ES+) Calculated for
C16H19ClN3O [M+H]+: 304.1217, found: 304.1211.
4.5.5. N-(2-chlorobenzyl)-6-(piperidin-1-yl)-pyridine-2-amine (8e)
Reaction of 14b with piperidine (128 mg, 1.5 eq.) gave compound 8e (160 mg, 53%) as a
light yellow oil. IR (cm-1): 3247 (NH str.), 2877 (CH str.), 1602 and 1579 (NH bend), 1441
(C=C); 1H NMR (500 MHz, CDCl3) δ 7.50 – 7.39 (m, 1H), 7.39 – 7.30 (m, 1H), 7.24 – 7.13
(m, 3H), 5.96 (d, J = 8.1 Hz, 1H), 5.69 (d, J = 7.8 Hz, 1H), 4.87 – 4.63 (m, 1H) , 4.56 (d, J =
6.0 Hz, 2H), 3.56 – 3.34 (m, 4H), 1.69 – 1.50 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 158.9,
157.3, 139.0, 137.4, 133.2, 129.3, 129.2, 128.1, 126.8, 95.7, 94.8, 46.3, 43.9, 25.5, 24.9.
HRMS (ES+) Calculated for C17H21ClN3 [M+H]+: 302.1424, found: 302.1420.
4.6. General procedure for the preparation of compounds 16a and 16b
18

ACCEPTED MANUSCRIPT
The appropriately substituted benzenesulfonyl chloride (10.0 mmol) was added dropwise to a
stirred ice-cold solution of 2-amino-6-bromopyridine 11 (1.62 g, 9.36 mmol) in acetonitrile
(20 ml) and stirred at 0°C for 20 min. The temperature was allowed to warm gradually to
room temperature and the reaction was stirred for a further 4 h. After removing the solvent
under reduced pressure, the crude product was dissolved in dichloromethane (20 ml) and
washed consecutively with saturated NaHCO3 solution (2 x 15 ml) and distilled water (2 x 15
ml). After drying the organic layer over anhydrous Na2SO4, the solvent was removed in
vacuo and the crude product purified by flash silica gel column chromatography, eluting
with 5 – 10% EtOAc/hexane.
4.6.1. N-(6-bromopyridin-2-yl)-2-chlorobenzenesulfonamide (16a)
Reaction of 2-chloro-benzenesulfonyl chloride (2.10 g, 10.0 mmol) gave compound 16a
(3.39 g, 98%) as a white crystalline compound. Mp: 168 - 169°C; IR (cm-1): 3431 and 3235
1
(NH stretch), 2924 (CH str.), 1631 (C=N), 1571 (NH bend), 1437 (C=C); H NMR (300
MHz, CDCl3) δ 8.21 – 8.16 (m, 1H), 7.82 (br s, 1H), 7.56 – 7.49 (m, 2H), 7.46 – 7.37 (m,
2H), 7.20 (dt, J = 8.2, 0.6 Hz, 1H), 7.14 (dt, J = 7.6, 0.6 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 149.8, 140.4, 140.2, 136.2, 134.6, 132.1, 132.0, 131.9, 127.1, 123.7, 109.8; HRMS (ES+)
Calculated for C11H9BrClN2O2S [M+H]+: 346.9257, found: 346.9246.
4.6.2. N-(6-bromopyridin-2-yl)-benzenesulfonamide (16b)
Reaction of benzenesulfonyl chloride (1.77 g, 10.0 mmol) gave compound 16b (3.09 g, 96%)
as a white crystalline compound. Mp: 111 - 113°C; IR (cm-1): 3315 (NH str.), 3071 (CH str.),
1
1584 (C=N), 1568 (NH bend), 1438 (C=C); H NMR (300 MHz, CDCl3) δ 7.99 – 7.90 (m,
2H), 7.71 (br s, 1H), 7.63 – 7.55 (m, 1H), 7.55 – 7.43 (m, 3H), 7.31 (dd, J = 8.1, 0.6 Hz, 1H),
7.15 (dd, J = 7.7, 0.8 Hz, 1H); 13C NMR (75 Hz, CDCl3) δ 150.4, 140.5, 140.1, 139.0, 133.6,
129.3, 127.4, 123.5, 110.1. HRMS (ES+) Calculated for C11H10BrN2O2S [M+H]+: 312.9646,
found: 312.9639.
4.7. General procedure for the preparation of compounds 9a-h
Tris-(dibenzylideneacetone)-di-palladium (0) [Pd2dba3], (19 mg, 2 mol %), rac-BINAP (38
mg, 6mol %), dioxane (3 – 5 ml, degassed) and a magnetic stirrer were added to an oven-
dried 10 ml round bottomed flask under nitrogen purge. The flask was sealed and heated with
stirring at 80°C in an oil bath (5 min). An appropriate sulfonamide 16a or b (1.0 mmol), an
amine (1.3 – 3.0 mmol) and potassium tert-butoxide (2.4 mmol) were added and the sealed
19

ACCEPTED MANUSCRIPT
reaction was heated at 120 – 135°C for 24 h. The reaction mixture was cooled to room
temperature, diluted with chloroform (15 ml) and filtered. The filtrate was washed
successively with saturated aqueous NaHCO3 (10 ml) and distilled water (2 x 10 ml). After
drying over Na2SO4, the solvent was removed in vacuo and the crude mixture was purified by
silica gel flash column chromatography, eluting the desired compound with 5 – 10%
EtOAc/hexane.
4.7.1. 2-Chloro-N-(6-(cyclohexylamino)-pyridin-2-yl)benzenesulfonamide (9a)
Reaction of 16a (348 mg, 1.0 mmol) with cyclohexylamine (198 mg, 2.0 eq.) gave compound
9a (234 mg, 64%) as a pale yellow oil. IR (cm-1): 3349 and 3244 (NH str.), 3064 (CH str.),
1612 and 1593 (CN bend str.), 1452 (C=C str.); 1H NMR (300 MHz, CDCl3) δ 8.14 (dd, J =
8.1, 0.9 Hz, 1H), 7.43 – 7.28 (m, 5H), 6.62 (d, J = 8.0 Hz, 1H), 5.85 (d, J = 8.3 Hz, 1H), 3.25
– 3.17 (m, 1H), 1.99 – 1.90 (m, 2H), 1.81 – 1.73 (m, 2H), 1.60 – 1.56 (m, 1H), 1.34 – 1.19
13
(m, 5H); C NMR (125 MHz, CDCl3) δ 153.5, 152.3, 143.3, 139.8, 132.4, 132.4, 131.7,
130.8, 126.3, 100.0, 96.2, 51.6, 32.3, 25.4, 24.9; HRMS (ES+) Calculated for C17H21ClN3O2S
[M+H]+: 366.1043, found: 366.1042.
4.7.2. N-(6-(benzylamino)-pyridin-2-yl)-2-chlorobenzenesulfonamide (9b)
Reaction of 16a (348 mg, 1.0 mmol) with benzylamine (161 mg, 1.5 eq.) gave compound 9b
(187 mg, 50%) as a pale brown oil. IR (cm-1): 3257 (NH str.), 3106 and 2928 (CH str.), 1602
1
(NH bend), 1428 (C=C str.); H NMR (500 MHz, CDCl3) δ 8.15 – 8.11 (m, 1H), 7.70 (br s,
1H), 7.44 – 7.38 (m, 2H), 7.34 – 7.22 (m, 8H), 6.69 (d, J = 8.4 Hz, 1H), 5.81 (d, J = 8.4 Hz,
13
1H), 4.39 (d, J = 5.4 Hz, 2H); C NMR (125 MHz, CDCl3) δ 153.8, 152.9, 143.1, 139.3,
137.4, 132.8, 132.2, 131.7, 130.9, 128.7, 127.4, 127.1, 126.5, 101.0, 97.4, 46.2; HRMS (ES+)
Calculated for C18H17ClN3O2S [M+H]+: 374.0730, found: 374.0726.
4.7.3. 2-Chloro-N-(6-(phenylamino)-pyridin-2-yl)benzenesulfonamide (9c)
Reaction of 16a (348 mg, 1.0 mmol) with aniline (140 mg, 1.5 eq.) gave compound 9c (208
mg, 58%) as a pale yellow solid. Mp: 107 - 109°C; IR (cm-1): 3350 and 3245 (NH str.), 3065
1
(CH str.), 1612, 1592 and 1538 (NH bend), 1452 and 1404 (C=C str.); H NMR (300 MHz,
CDCl3) δ 9.01 (s, 1H), 8.22 – 8.12 (m, 1H), 7.53 – 7.20 (m, 9H), 7.16 – 7.07 (m, 1H), 6.89 –
6.81 (m, 1H), 6.41 – 6.34 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 152.8, 152.1, 143.0, 138.9,
138.3, 133.0, 132.2, 131.8, 131.0, 129.4, 126.6, 124.6, 122.2, 102.8, 99.4; HRMS (ES+)
Calculated for C17H15ClN3O2S [M+H]+: 360.0574, found: 360.0572.
20

ACCEPTED MANUSCRIPT
4.7.4. 2-Chloro-N-(6-morpholinopyridin-2-yl)benzenesulfonamide (9d)
Reaction of 16a (348 mg, 1.0 mmol) with morpholine (261 mg, 3.0 eq.) gave compound 9d
(279 mg, 79%) as a pale brown oil which solidified on drying. Mp: 178-180°C; IR (cm-1):
3154 (NH str.), 3093, 2873 and 2845 (CH str.), 1596 (C=N), 1573 (NH bend), 1430 (C=C
str.); 1H NMR (300 MHz, CDCl3) δ 8.22 – 8.12 (m, 1H), 7.63 – 7.50 (m, 1H), 7.49 – 7.44 (m,
2H), 7.42 – 7.31 (m, 2H), 6.47 (d, J = 7.8 Hz, 1H), 6.24 (d, J = 8.3 Hz, 1H), 3.80 – 3.68 (m,
13
4H), 3.41 – 3.30 (m, 4H); C NMR (75 MHz, CDCl3) δ 158.3, 148.4, 139.8, 137.0, 134.0,
131.9, 131.8, 131.7, 126.9, 102.1, 100.6, 66.5, 45.2; HRMS (ES+) Calculated for
C15H17ClN3O3S [M+H]+: 354.0679, found: 354.0677.
4.7.5. 2-Chloro-N-(6-(piperidin-1-yl)-pyridin-2-yl)benzenesulfonamide (9e)
Reaction of 16a (348 mg, 1.0 mmol) with piperidine (255 mg, 3.0 eq.) gave compound 9e
(200 mg, 57%) as a pale yellow solid. Mp: 126 - 128°C; IR (cm-1): 3229 (NH str.), 2930 and
2852 (CH str.), 1598 (C=N), 1569 (NH bend), 1437 (C=C str.); 1H NMR (500 MHz, CDCl3)
δ 8.18 – 8.15 (m, 1H), 7.54 – 7.43 (m, 3H), 7.39 – 7.34 (m, 1H), 7.30 (dd, J = 8.4, 7.8 Hz,
1H), 6.34 (d, J = 7.7 Hz, 1H), 6.21 (d, J = 8.4 Hz, 1H), 3.41 – 3.36 (m, 4H), 1.64 – 1.50 (m,
13
6H); C NMR (75 MHz, CDCl3) δ 157.6, 148.7, 139.8, 137.4, 133.7, 131.9, 131.7, 131.6,
126.8, 101.6, 99.6, 46.0, 25.3, 24.6. HRMS (ES+) Calculated for C16H19ClN3O2S [M+H]+:
352.0887, found: 352.0885.
4.7.6. N-(6-(cyclohexylamino)-pyridin-2-yl)benzenesulfonamide (9f)
Reaction of 16b (313 mg, 1.0 mmol) with cyclohexylamine (198 mg, 2.0 eq.) gave compound
9f (216 mg, 65%) as a pale yellow oil. IR (cm-1): 3251 (NH str.), 3103, 2930 and 2854 (CH
1
str.), 1600 (C=N), 1540 (NH bend), 1445 (C=C str.), H NMR (500 MHz, CDCl3) δ 8.98 –
7.91 (m, 2H), 7.58 (br s, 1H), 7.51 – 7.39 (m, 3H), 7.34 (t, J = 8.4 Hz, 1H), 6.59 (d, J = 8.1
Hz, 1H), 5.83 (d, J = 8.3 Hz, 1H), 3.19 (s, 1H), 1.99 – 1.88 (m, 2H), 1.80 – 1.70 (m, 2H),
1.61 – 1.52 (m, 1H), 1.35 – 1.18 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 154.4, 151.9, 143.9,
142.9, 131.5, 128.6, 126.8, 100.2, 95.5, 51.6, 32.1, 25.3, 24.7. HRMS (ES+) Calculated for
C17H22N3O2S [M+H]+: 332.1433, found: 332.1426.
4.7.7. N-(6-morpholinopyridin-2-yl)benzenesulfonamide (9g)
Reaction of 16b (313 mg, 1.0 mmol) with morpholine (131 mg, 1.5 eq.) gave compound 9g
(179 mg, 56%) as a pale yellow oil. IR (cm-1): 3212 (NH str.), 2918, 2891and 2857 (CH str.),
21

ACCEPTED MANUSCRIPT
1
1601 (C=N), 1571 (NH bend), 1435 (C=C str.); H NMR (300 MHz, CDCl3) δ 7.98 – 7.90
(m, 2H), 7.73 – 7.35 (m, 5H), 6.57 (d, J = 7.8 Hz, 1H), 6.25 (d, J = 8.3 Hz, 1H), 3.79 – 3.68
13
(m, 4H), 3.41 – 3.30 (m, 4H); C NMR (75 MHz, CDCl3) δ 158.4, 149.0, 139.9, 139.9,
133.0, 129.0, 127.3, 101.9, 100.3, 66.6, 45.3; HRMS (ES+) Calculated for C15H18N3O3S
[M+H]+: 320.1069, found: 320.1069.
4.7.8. N-(6-(piperidin-1-yl)-pyridin-2-yl)benzenesulfonamide (9h)
Reaction of 16b (313 mg, 1.0 mmol) with piperidine (128 mg, 1.5 eq.) gave compound 9h
(194 mg, 61%) as a pale yellow solid. Mp: 133 - 135°C; IR (cm-1): 3236 (NH str.), 2935 and
2854 (CH str.), 1599 (C=N), 1565 (NH bend), 1440 (C=C str.); 1H NMR (300 MHz, CDCl3)
δ 8.03 -7.83 (m, 2H), 7.60 – 7.39 (m, 4H), 7.32 (t, J = 8.4 Hz, 1H), 6.43 (d, J = 7.7 Hz, 1H),
13
6.32 (d, J = 8.4 Hz, 1H), 3.51 – 3.30 (m, 4H), 1.65 – 1.49 (m, 6H); C NMR (75 MHz,
CDCl3) δ 158.1, 148.9, 140.2, 139.7, 132.8, 128.9, 127.3, 101.7, 99.1, 46.0, 25.3, 24.6;
HRMS (ES+) Calculated for C16H20N3O2S [M+H]+: 318.1276, found: 318.1277.
4.8. General procedure for the preparation of compounds 17a-e
The same method was used as for the preparation of compounds 7a-i except that the sealed
reaction was heated at 130°C for 24h.
4.8.1. N-(6-butoxypyridin-2-yl)-2-chlorobenzamide (17a)
Reaction of compound 12a (310 mg, 1.0 mmol) with n-butanol (89 mg, 1.2 eq.) yielded
compound 17a (138 mg, 45%) as a colourless oil. IR (cm-1): 3275 (NH br str.), 2958 and
1
2872 (CH str.), 1676 (C=O str.), 1591 (C=N), 1575 (NH bend), 1523 (C=C); H NMR (300
MHz, CDCl3) δ 8.30 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.71 (dd, J = 7.4, 1.7 Hz, 1H), 7.64 (t,
J = 8.0 Hz, 1H), 7.48 – 7.32 (m, 3H), 6.52 (dd, J = 8.1, 0.6 Hz, 1H), 4.18 (t, J = 6.6 Hz, 2H),
13
1.77 – 1.67 (m, 2H), 1.53 – 1.37 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); C NMR (75 MHz,
CDCl3) δ 164.6, 162.9, 148.7, 140.9, 135.1, 131.8, 130.9, 130.5, 130.0, 127.2, 106.6, 105.7,
65.9, 31.1, 19.3, 13.9; HRMS (ES+) Calculated for C16H18ClN2O2 [M+H]+: 305.1057, found:
305.1047.
4.8.2. 2-Chloro-N-(6-phenoxypyridin-2-yl)benzamide (17b)
Reaction of compound 12a (310 mg, 1.0 mmol) with phenol (123 mg, 1.3 eq.) yielded
compound 17b (231 mg, 70%) as a pale brown oil. IR (cm-1): 3176 (NH str.), 3075 (CH str.),
1684 (C=O), 1563 (NH bend), 1426 (C=C); 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.34
22

ACCEPTED MANUSCRIPT
(d, J = 8.2 Hz, 1H), 7.73 – 7.66 (m, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.49 – 7.42 (m, 2H), 7.42 –
7.33 (m, 2H), 7.31 – 7.17 (m, 2H), 6.95 – 6.87 (m, 1H), 6.86 – 6.79 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 164.9, 155.6, 151.0, 140.8, 139.4, 134.3, 132.2, 131.0, 130.6, 129.9, 129.6,
127.3, 124.2, 120.6, 115.3, 112.7; HRMS (ES+) Calculated for C18H14ClN2O2 [M+H]+:
325.0744, found: 325.0744.
4.8.3. N-(6-(benzyloxy)-pyridin-2-yl)-2-chlorobenzamide (17c)
Reaction of compound 12a (310 mg, 1.0 mmol) with benzyl alcohol (141 mg, 1.3 eq.) yielded
compound 17c (169 mg, 52%) as a brown oil. IR (cm-1): 3411 (NH str.), 3060 and 2947 (CH
1
str.), 1669 (C=O ), 1605 (C=N), 1574 (NH bend), 1430 (C=C); H NMR (500 MHz, CDCl3)
δ 8.29 (s, 1H), 7.96 – 7.90 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.53 – 7.47
(m, 2H), 7.46 –7.41 (m, 2H), 7.40 – 7.36 (m, 2H), 7.35 – 7.30 (m, 1H), 6.62 – 6.58 (m, 1H),
5.33 – 5.27 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 165.4, 162.4, 149.1, 141.1, 137.1, 134.5,
132.2, 128.9, 128.5, 128.5, 127.9, 127.9, 127.8, 127.1, 106.6, 106.0, 67.8; HRMS (ES+)
Calculated for C19H16ClN2O2 [M+H]+: 339.0900, found: 339.0892.
4.8.4. 2-Chloro-N-(6-phenylthio)-pyridin-2-yl)benzamide (17d)
Reaction of compound 12a (310 mg, 1.0 mmol) with thiophenol (143 mg, 1.3 eq.) yielded
compound 17d (237 mg, 63%) as a pale brown oil. IR (cm-1): 3225 (NH str.), 3058 and 2936
(CH str.), 1649 (C=O ), 1563 (NH bend), 1429 (C=C); 1H NMR (300 MHz, CDCl3) δ 8.49 (s,
1H), 8.07 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 7.6, 1.6 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.53 (t, J =
13
8.0 Hz, 1H), 7.48 – 7.28 (m, 6H), 6.64 (d, J = 7.8 Hz, 1H); C NMR (75 MHz, CDCl3) δ
164.8, 159.8, 150.6, 139.1, 135.0, 134.8, 131.9, 131.0, 130.5, 129.9, 129.61, 129.57, 129.2,
127.2, 117.6, 110.1; HRMS (ES+) Calculated for C18H14ClN2OS [M+H]+: 341.0515, found:
341.0506.
4.8.5. N-(6-benzylthio)-pyridin-2-yl)-2-chlorobenzamide (17e)
Reaction of compound 12a (310 mg, 1.0 mmol) with benzylthiol (161 mg, 1.3 eq.) yielded
compound 17e (203 mg, 52%) as a pale brown oil. IR (cm-1): 3406 (NH str.), 3062 (CH str.),
1683 (C=O), 1587 (C=N), 1561 (NH bend), 1429 (C=C); 1H NMR (300 MHz, CDCl3) δ 8.51
(s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 7.3, 1.8 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.47
– 7.33 (m, 5H), 7.32 – 7.19 (m, 3H), 6.95 (d, J = 7.7, 1H), 4.34 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 164.5, 157.3, 150.6, 138.5, 137.8, 134.7, 132.0, 130.8, 130.5, 130.3, 128.9, 128.5,
23

ACCEPTED MANUSCRIPT
127.3, 127.2, 118.4, 109.6, 34.5; HRMS (ES+) Calculated for C19H16ClN2OS [M+H]+:
355.0672, found: 355.0660.
4.9. General procedure for the preparation of compounds 18a-e
The same method was used as for the preparation of compounds 7a-i except that the sealed
reaction was heated at 135 - 140°C for 24 h.
4.9.1. 6-Butoxy-N-(2-chlorobenzyl)pyridin-2-amine (18a)
Reaction of compound 14b (427 mg, 1.0 mmol) with n-butanol (111 mg, 1.5 eq.) gave
compound 18a (190 mg, 65%) as a pale yellow oil. IR (cm-1): 2959 and 2873 (CH str.), 1580
(C=N), 1442 (C=C); 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.27 (m, 3H), 7.24 – 7.12 (m, 2H),
6.02 (d, J = 7.9 Hz, 1H), 5.91 (d, J = 7.9 Hz, 1H), 4.84 (t, J = 5.5 Hz, 1H), 4.58 (d, J = 6.2
Hz, 2H), 4.17 (t, J = 6.7, 6.7 Hz, 2H), 1.78 – 1.63 (m, 2H), 1.45 – 1.39 (m, 2H), 0.94 (t, J =
7.3, 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 157.3, 140.0, 136.9, 133.3, 129.4,
129.1, 128.3, 126.8, 98.1, 97.8, 65.5, 44.0, 31.3, 19.3, 13.9; HRMS (ES+) Calculated for
C16H20ClN2O [M+H]+: 291.1264, found: 291.1264.
4.9.2. N-(2-chlorobenzyl)-6-phenoxypyridin-2-amine (18b)
Reaction of compound 14b (427 mg, 1.0 mmol) with phenol (141 mg, 1.5 eq.) gave
compound 18b (189 mg, 61%) as a pale yellow oil. IR (cm-1): 3267 (NH str.), 3065 (CH str.),
1
1590 and 1560 (C=N), 1428 (C=C); H NMR (300 MHz, CDCl3) δ 7.55 – 7.06 (m, 10H),
6.75 (d, J = 7.5 Hz, 1H), 6.25 (d, J = 8.2 Hz, 1H), 5.16 (t, J = 6.3 Hz, 1H), 4.57 (d, J = 6.2
13
Hz, 2H); C NMR (75 MHz, CDCl3) δ 160.7, 158.5, 155.1, 140.3, 139.6, 135.8, 133.5,
129.6, 129.4, 129.0, 128.7, 128.4, 127.0, 116.4, 104.8, 44.0; HRMS (ES+) Calculated for
C18H16ClN2O [M+H]+: 311.0951, found: 311.0949.
4.9.3. 6-Benzyloxy-N-(2-chlorobenzyl)pyridin-2-amine (18c)
Reaction of compound 14b (427 mg, 1.0 mmol) with benzyl alcohol (141 mg, 1.3 eq.) gave
compound 18c (205 mg, 63%) as a pale brown oil. IR (cm-1): 3329, 3064, 2926, 1593, 1566,
1418, 1215; 1H NMR (CDCl3, 500 MHz) δ 7.40 – 7.25 (m, 8H), 7.20 – 7.15 (m, 2H), 6.11 –
6.09 (dd, J = 8.0, 5.0 Hz, 1H), 5.93 (dd, J = 7.5, 5.0 Hz, 1H), 5.28 (s, 2H), 4.87 – 4.81 (m,
13
1H), 4.58 (d, J = 5.3 Hz, 2H); C NMR (125 MHz, CDCl3) δ 163.0, 157.1, 140.1, 137.9,
136.9, 133.3, 129.4, 129.1, 128.4, 128.3, 127.8, 127.5, 126.8, 98.6, 98.4, 67.1, 43.9; HRMS
(ES+) Calculated for C19H18ClN2O [M+H]+: 325.1108, found: 325.1121.
24

ACCEPTED MANUSCRIPT
4.9.4. N-(2-chloro-benzyl)-6-(phenylthio)pyridin-2-amine (18d)
Reaction of compound 14b (427 mg, 1.0 mmol) with thiophenol (143 mg, 1.3 eq.) gave
compound 18d (228 mg, 70%) as a pale brown oil. IR (cm-1): 3261 (NH str.), 3066 (CH str.),
1
1591 and 1560 (C=N), 1428 (C=C); H NMR (300 MHz, CDCl3) δ 7.55 – 7.05 (m, 10H),
6.73 (d, J = 7.5 Hz, 1H), 6.23 (d, J = 8.2 Hz, 1H), 5.35 (t, J = 6.3 Hz, 1H), 4.57 (d, J = 6.3
13
Hz, 2H); C NMR (75 MHz, CDCl3) δ 158.5, 140.2, 139.6, 135.8, 133.4, 132.8, 129.5,
129.3, 128.8, 128.7, 128.4, 127.5, 127.0, 116.3, 104.7, 44.0; HRMS (ES+) Calculated for
C18H16ClN2S [M+H]+: 327.0723, found: 327.0721.
4.9.5. 6-Benzylthio-N-(2-chlorobenzyl)-pyridin-2-amine (18e)
Reaction of compound 14b (427 mg, 1.0 mmol) with benzylthiol (161 mg, 1.3 eq.) gave
compound 18e (299 mg, 88%) as a pale yellow oil. IR (cm-1): 3422 (NH str.), 3060 and 3027
(CH str.), 1583 (C=N), 1567 (NH bend), 1441 (C=C); 1H NMR (300 MHz, CDCl3) δ 7.43 –
7.12 (m, 10H), 6.48 (dd, J = 7.5, 0.6 Hz, 1H), 6.06 (dd, J = 8.1, 0.6 Hz, 1H), 4.95 (t, J = 5.9
13
Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 4.32 (s, 2H); C NMR (75 MHz, CDCl3) δ 157.9, 156.6,
138.5, 137.6, 136.7, 133.2, 129.4, 129.0, 128.8, 128.4, 128.3, 126.9, 126.8, 110.9, 102.7,
43.7, 34.2; HRMS (ES+) Calculated for C19H18ClN2S [M+H]+: 341.0879, found: 341.0874.
4.10. General procedure for the preparation of compounds 19a-g
The same method was used as for the preparation of compounds 9a-h except that the sealed
reaction was heated at 135 - 140°C for 24 h.
4.10.1. N-(6-butoxypyridin-2yl)-2-chloro-benzenesulfonamide (19a)
Reaction of compound 16a (347 mg, 1.0 mmol) with n-butanol (148 mg, 2.0 eq.) gave
compound 19a (211 mg, 62%) as a pale yellow oil. IR (cm-1): 3243 (NH str.), 2960 and 2931
(CH str.), 1594 (NH bend), 1441 (C=C); 1H NMR (500 MHz, CDCl3) δ 8.19 – 8.14 (m, 1H),
7.59 – 7.51 (m, 1H), 7.50 – 7.34 (m, 4H), 6.69 (d, J = 7.7 Hz, 1H), 6.36 (d, J = 8.2 Hz, 1H)
4.07 (t, J = 6.6 Hz, 2H), 1.69 – 1.62 (m, 2H), 1.47 – 1.33 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 163.2, 147.7, 140.6, 136.7, 134.1, 132.0, 131.9, 131.8, 126.9,
106.3, 103.3, 66.0, 30.9, 19.2, 13.9; HRMS (ES+) Calculated for C15H18ClN2O3S [M+H]+:
341.0727, found: 341.00719.
4.10.2. N-(6-(benzyloxy)-pyridin-2-yl)-2-chloro-benzenesulfonamide (19b)
25

ACCEPTED MANUSCRIPT
Reaction of compound 16a (347 mg, 1.0 mmol) with benzyl alcohol (216 mg, 2.0 eq.) gave
compound 19b (300 mg, 80%) as a brown solid. Mp: 121 - 123°C; IR (cm-1): 3247 (NH str.),
1
2877 (CH str.), 1602 (C=N), 1579 (NH bend), 1441 (C=C); H NMR (500 MHz, CDCl3) δ
8.16 (dt, J = 7.9, 1.0 Hz, 1H), 7.50 – 7.42 (m, 4H), 7.39 – 7.29 (m, 6H), 6.74 (d, J = 7.7 Hz,
13
1H), 6.45 (d, J = 8.1 Hz, 1H), 5.16 (s, 2H); C NMR (125 MHz, CDCl3) δ 162.7, 147.6,
140.8, 136.9, 136.6, 134.2, 131.9, 131.8, 131.8, 128.5, 128.0, 127.9, 127.0, 106.7, 103.7,
67.8; HRMS (ES+) Calculated for C18H16ClN2O3S [M+H]+: 375.0570, found: 375.0568.
4.10.3. 2-Chloro-N-(6-(phenylthio)-pyridin-2-yl)benzenesulfonamide (19c)
Reaction of compound 16a (347 mg, 1.0 mmol) with thiophenol (330 mg, 3.0 eq.) gave
compound 19c (312 mg, 83%) as a brown solid. Mp: 129 - 131°C; IR (cm-1): 3231 (NH str.),
1
2924 (CH str.), 1570 (C=N), 1435 (C=C); H NMR (500 MHz, CDCl3) δ 8.11 – 8.08 (m,
1H), 7.58 (br s, 1H), 7.54 – 7.46 (m, 4H), 7.43 – 7.35 (m, 4H), 7.31(t, J = 7.5 Hz, 1H), 6.92
13
13
(d, J = 8.1Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H); C NMR (125 MHz, CDCl3) C NMR (125
MHz, CDCl3) δ 149.7, 138.9, 135.1, 134.6, 134.2, 132.0, 131.9, 131.7, 130.0, 129.6, 129.4,
127.0, 123.7, 116.8, 107.6; HRMS (ES+) Calculated for C17H14ClN2O2S2 [M+H]+: 377.0185,
found: 377.0177.
4.10.4. N-(6-(benzylthio)-pyridin-2-yl)-2-chlorobenzenesulfonamide (19d)
Reaction of compound 16a (347 mg, 1.0 mmol) with benzylthiol (372 mg, 3.0 eq.) gave
compound 19d (281 mg, 72%) as a pale brown solid. Mp: 122 - 123°C; IR (cm-1): 3256 (NH
str.), 2929 (CH str.), 1565 (NH bend), 1430 (C=C); 1H NMR (500 MHz, CDCl3) δ 8.16 – 812
(m, 1H), 7.82 – 7.70 (br m, 1H), 7.48 – 7.44 (m, 2H), 7.36 – 7.20 (m, 7H), 6.91 (d, J = 8.0
Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 4.29 – 4.19 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 149.4,
138.3, 137.7, 136.5, 134.3, 131.84, 131.80, 129.1, 128.8, 128.6, 128.5, 127.2, 127.1, 117.9,
107.3, 34.2; HRMS (ES+) Calculated for C18H16ClN2O2S2 [M+H]+: 391.0342, found:
391.0339.
4.10.5. N-(6-butoxypyridin-2-yl)-benzenesulfonamide (19e)
Reaction of compound 16b (347 mg, 1.0 mmol) with n-butanol (222 mg, 3.0 eq.) gave
compound 19e (162 mg, 53%) as a pale brown solid. Mp: 94 - 96°C; IR (cm-1): 3237 (NH
1
str.), 2962 and 2931 (CH str.), 1613 (C=N), 1574 (NH bend), 1441 (C=C); H NMR (300
MHz, CDCl3) δ 7.99 -7.91 (m, 2H), 7.61 – 7.52 (m, 1H), 7.51 – 7.41 (m, 3H), 7.31 (br s, 1H),
6.77 (d, J = 7.7 Hz, 1H), 6.37 (d, J = 8.1 Hz, 1H), 4.05 (t, J = 6.6 Hz, 2H), 1.70 – 1.58 (m,
26

ACCEPTED MANUSCRIPT
13
2H), 1.45 – 1.31 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); C NMR (75 MHz, CDCl3) δ 163.3,
148.2, 140.6, 139.7, 133.1, 129.0, 127.3, 105.9, 103.2, 66.0, 30.9, 19.2, 13.8; HRMS (ES+)
Calculated for C15H19N2O3S [M+H]+: 307.1116, found: 307.1114.
4.10.6 N-(6-(benzyloxy)-pyridin-2-yl)-benzenesulfonamide (19f)
Reaction of compound 16b (347 mg, 1.0 mmol) with benzyl alcohol (141 mg, 1.3 eq.) gave
compound 19f (218 mg, 64%) as a pale brown solid. Mp: 133 - 135°C; IR (cm-1): 3246 (NH
1
str.), 2877 (CH str.), 1603 (C=N), 1580 (NH bend), 1441 (C=C); H NMR (300 MHz,
CDCl3) δ 7.97 – 7.91 (m, 2H), 7.62 – 7.40 (m, 5H), 7.39 – 7.23 (m, 5H), 6.78 (dd, J = 7.8, 0.7
13
Hz, 1H), 6.43 (dd, J = 8.1, 0.6 Hz, 1H), 5.12 (s, 2H); C NMR (75 MHz, CDCl3) δ 162.7,
148.2, 140.8, 139.7, 136.9, 133.1, 129.0, 128.4, 127.91, 127.88, 127.3, 106.2, 103.6, 67.8;
HRMS (ES+) Calculated for C18H17N2O3S [M+H]+: 341.0960, found: 341.0954.
4.11. N-(6-(bromopyridin-2-yl)-4-cyano-2-fluorobenzamide (20)
4-Cyano-2-fluorobenzoic acid (0.5 g, 3.0 mmol) was quantitatively converted to a reactive
acyl chloride which was further reacted with 2-amino-6-bromopyridine 11 (0.52 g, 3.0
mmol), as described for compound 12, to give compound 20 as a white crystalline solid
(1.012 g, 97%). Mp: 210 – 211°C; IR (cm-1): 3436 (NH str.), 3097 and 2923 (CH str.), 2238
(CN), 1686 (C=O), 1621 (C=N), 1565 (NH bend), 1437 (C=C); 1H NMR (CDCl3, 500 MHz)
δ 9.00 (d, J = 12.2 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.31 – 8.24 (m, 2H), 7.88 (dd, J = 8.8,
13
2.4 Hz, 1H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.54 (dd, J = 11.0, 1.4 Hz, 1H); C NMR (125
MHz, CDCl3) δ 159.620 (d, JC-F = 250 Hz), 159.617 (d, JC-F = 3 Hz), 149.4, 149.1, 141.0,
133.3 (d, JC-F = 2 Hz), 128.8 (d, JC-F = 4 Hz), 125.3 (d, JC-F = 12 Hz), 120.4 (d, JC-F = 28 Hz),
117.5 (d, JC-F = 10 Hz), 116.4, 115.9, 115.8; HRMS (ES+) Calculated for C13H8BrFN3O
[M+H]+: 319.9835, found: 319.9831.
4.12. N-(6-(bromopyridin-2-yl)-4-cyano-2-(piperidin-1-yl)benzamide (21)
Reaction of compound 20 (319 mg, 1.0 mmol) with piperidine (111 mg, 1.3 eq.), as described
for compounds 7a-i, gave compound 21 (327 mg, 85%) as yellow crystals. Mp: 164 - 165°C;
IR (cm-1): 3430 (NH str.), 2937 and 2856 (CH str.), 2228 (CN str.), 1677 (C=O), 1605
(C=N), 1557 (NH bend), 1422 (C=C); 1H NMR (500 MHz, CDCl3) δ 12.92 (s, 1H), 8.30 (t, J
= 8.0 Hz, 2H), 7.60 – 7.53 (m, 3H), 7.22 (d, J = 7.6 Hz, 1H), 3.04 – 2.97 (m, 4H), 1.99 –
1.91 (m, 4H), 1.72 – 1.60 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 162.7, 153.1, 151.7, 140.4,
27

ACCEPTED MANUSCRIPT
139.6, 132.5, 131.1, 128.1, 125.1, 123.5, 117.8, 116.2, 112.9, 55.2, 25.6, 23.7; HRMS (ES+)
Calculated for C18H18BrN4O [M+H]+: 385.0664, found: 385.0655.
4.12.1. Alternative preparation of compound 21
N-(6-(bromopyridin-2-yl)-4-cyano-2-fluorobenzamide 20 (319 mg, 1.0 mmol), dioxane (10
ml, degassed), piperidine (128 mg, 1.5 eq.) and a magnetic stirrer were added to an oven-
dried 10 ml round-bottomed flask under nitrogen purge. The mixture was stirred at 60°C in
an oil bath (5 min). A base, KHMDS (2.5 ml of 0.5 M solution in hexane) or KOtBu (269 mg,
2.4 eq.), was added in small portions and the reaction heated at 110°C for 3 h. After cooling
to room temperature, the reaction mixture was diluted with dichloromethane or chloroform
(15 ml) and filtered. The filtrate was washed successively with saturated aqueous NaHCO3
(10 ml) and distilled water (2 x 10 ml), dried over anhydrous Na2SO4 and the solvent
removed in vacuo to give a pale yellow solid 21 (385 mg, 99%).
4.13. 4-Cyano-2-(piperidin-1-yl)-N-(6-(-piperidin-1-yl)pyridin-2-yl)benzamide (22)
Reaction of compound 21 (385 mg, 1.0 mmol) with piperidine (111 mg, 1.3 eq.), as described
for compounds 7a-i, gave compound 22 (331 mg, 85%) as pale yellow crystals. Mp: 171-
173°C; IR (cm-1): 3130 (NH str.), 2927 and 2833 (CH str.), 2229 (CN str.), 1668 (C=O),
1
1599 (C=N), 1566 (NH bend), 1440 (C=C); H NMR (300 MHz, CDCl3) δ 12.31 (s, 1H),
8.34 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.56 – 7.47 (m, 3H), 6.44 (d, J = 8.2 Hz,
1H), 3.60 – 3.50 (m, 4H), 3.07 – 2.95 (m, 4H), 2.05 – 1.90 (m, 4H), 1.71 – 1.55 (m, 8H); 13C
NMR (75 MHz, CDCl3) δ 162.4, 158.1, 153.0, 149.9, 139.6, 132.6, 132.0, 127.9, 124.6,
118.1, 115.6, 103.0, 102.5, 55.1, 46.1, 25.7, 25.4, 24.9, 23.7; HRMS (ES+) Calculated for
C23H28N5O [M+H]+: 390.2294, found: 390.2296.
Acknowledgements
The authors would like to thank Prof Lynn Morris, National Institute for Communicable
Diseases, for guidance relating to the antiviral assay. Funding from the South African
Medical Research Council (MRC), National Research Foundation (NRF), NHLS Research
Trust and the University of the Witwatersrand is gratefully acknowledged.
Supplementary data
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