Exploiting C–H borylation for the multidirectional elaboration of 2-halopyridines

Article abstract of DOI:10.1016/j.tet.2019.130836

Regioselectively polysubstituted pyridines can be efficiently accessed from 2-halopyridines via a sequence involving C–H borylation, Suzuki-Miyaura cross-coupling and nucleophilic aromatic substitution chemistry.

Full text of DOI:10.1016/j.tet.2019.130836

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Exploiting C–H borylation for the multidirectional elaboration of 2-halopyridines
Jonathan A. Reuven, Omar A. Salih, Scott A. Sadler, Carys L. Thomas, Patrick G.
Steel
PII:
S0040-4020(19)31244-X
https://doi.org/10.1016/j.tet.2019.130836
TET 130836
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 September 2019
Revised Date: 20 November 2019
Accepted Date: 25 November 2019
Please cite this article as: Reuven JA, Salih OA, Sadler SA, Thomas CL, Steel PG, Exploiting C–
H borylation for the multidirectional elaboration of 2-halopyridines, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.130836.
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Exploiting C-H Borylation for the Multidirectional Elaboration of 2-Halopyridines
Jonathan A. Reuven, jonathan.a.reuven@durham.ac.uka
Omar A. Salih, omar_hh2005@yahoo.coma,b
Scott. A. Sadler, scott.sadler1989@hotmail.coma
Carys L. Thomas, syrac_@hotmail.coma
and
Patrick G. Steel* p.g.steel@durham.ac.uka
aDepartment of Chemistry, University of Durham, Science Laboratories, Lower Mountjoy,
South Road, Durham, DH1 3LE
b Department of Chemistry, College of Education for Pure Sciences, Mosul University, Iraq
*Corresponding Author Address
Professor Patrick Steel
Department of Chemistry
University of Durham
Science Laboratories
Lower Mountjoy
South Road, Durham
DH1 3LE
p.g.steel@durham.ac.uk
1

Graphical Abstract
2

Exploiting C-H Borylation for the Multidirectional Elaboration of 2-Halopyridines
Jonathan A. Reuvena, Omar A. Saliha,b, Scott. A. Sadlera, Carys L. Thomasa, and Patrick G.
Steela,*
* Corresponding Author: Department of Chemistry, University of Durham, Science
Laboratories, Lower Mountjoy, South Road, Durham, DH1 3LE; email
p.g.steel@durham.ac.uk
3

aDepartment of Chemistry, University of Durham, Science Laboratories, Lower Mountjoy,
South Road, Durham, DH1 3LE
b Department of Chemistry, College of Education for Pure Sciences, Mosul University, Iraq
p.g.steel@durham.ac.uk
Abstract
Regioselectively polysubstituted pyridines can be efficiently accessed from 2-halopyridines
via a sequence involving C-H borylation, Suzuki-Miyaura cross-coupling and nucleophilic
aromatic substitution chemistry.
Dedication
Dedicated to Professor Steve Davies in recognition of his outstanding contributions to
advancing organic chemistry though both his teaching and his research.
Keywords
Pyridine; C-H Borylation; Suzuki-Miyaura; Multidirectional synthesis
Introduction
The pyridine ring represents an essential structural component of many functional molecules
including sensors, pharmaceuticals, agrochemicals, ligands for catalysis etc and is also found
in numerous natural products (Fig. 1). 1,2,3,4
Figure 1. Representative functional pyridines.
4

As such, methods to synthesise functionalised pyridines are of great value and much effort
has been applied towards this effect.5-11 Given the low reactivity of the electron deficient
azinyl ring towards electrophilic aromatic substitution, most routes to substituted pyridines
involve de novo synthesis with substituents and substitution patterns determined by the
building blocks employed. However, the ability to manipulate a preformed pyridine ring is
particularly valuable for late stage diversification. Among the various strategies for preparing
polyfunctionalised pyridines in this way are ring metalation with various strong bases,12,13
radical substitution14,15 and transition metal mediated C-H activation. 16,11 Whilst each has its
merit, the last is particularly attractive providing both high atom and step efficiency and
represent the ideal for green sustainable processes. Reflecting the versatility of the resulting
arylboronate esters for further downstream transformations and the functional group
tolerance of the process, Ir catalysed C-H borylation is a particularly attractive option for
elaboration of a preformed pyridine ring.17,11 First reported by Miyaura and Ishiyama in
2002,18,19 the borylation of pyridine is challenged by the Lewis basicity of the azinyl nitrogen
atom which can coordinate to and inhibit the catalytically active species. Moreover, the
azinyl nitrogen also affects both the regiochemistry of pyridine borylation disfavouring
substitution at the 2 and 6 positions and also rendering the products unstable with respect to
protodeborylation.20-23 In recent work we have shown this effect can be modulated by the
presence of an electron withdrawing 2-halo substituent which, not only sterically protects the
catalyst by blocking co-ordination to the iridium centre but also lowers the basicity of the
azinyl lone pair enhancing reactivity at the α-positions and increasing stability to
protodeborylation.24 The resultant 2-halopyridine boronate esters are versatile building blocks
for multi-directional elaboration and in this report we demonstrate this concept with the
synthesis of a diverse set of trifunctional pyridine scaffolds.
Results and Discussion
Building on our earlier work, initial studies focused on the borylation of simple 2,4-
disubstituted pyridines. The borylation of 2-chloro-4-trifluoromethyl- and 2-chloro-4-
tertbutylpyridine 1 and 2 (Table 1), using [Ir(cod)OMe]2 (1.5 mol%), dtbpy (3 mol%) and
B2Pin2 in THF, occurred as predicted at the sterically uninhibited 6-position. Although
adjacent to the azinyl nitrogen atom, the stabilising effect of the 2-chloro substituent allowed
the isolation of the boronate ester which could be identified by a characteristic downfield
1
shift of the signal for the adjacent 5-hydrogen in the H NMR spectrum. Whilst sufficiently
5

stable to be analysed as a crude product, attempts to chromatographically purify this
compound were complicated by significant protodeborylation and it was more effective to
use the crude reaction mixture directly in subsequent steps. Using the Suzuki-Miyaura
reaction as a classic exemplar transformation, reaction with 4-iodo-nitrobenzene (1.5 equiv.)
in the presence of PdCl2(dppf) (5 mol%) as the precatalyst afforded the desired biaryl 5z in
58% yield over the two steps (Table 1, entry 1). A range of arenes and heteroarenes (Fig. 2a),
including those containing both electron withdrawing and donating substituents, proved
viable giving moderate to good yields under these standard conditions. Having exploited the
ability of the halogen to enable and direct the C-H borylation, it was then of interest to use
this as a handle for further functionalisation. Using pyrrolidine as a test substrate, efficient
reaction could be achieved by simply heating the halopyridine with an excess of the amine in
THF in a sealed microwave vessel for 60 minutes. This proved to be a general observation
and was extended to include a range of amines (Fig. 2b), including primary, secondary cyclic
and acyclic alkyl amines but not aniline. Attempts to carry out the whole sequence in a single
operation were possible (Table 1 entry 6) but generally lead to more complex crude reaction
mixtures and slightly lower overall yields.
Figure 2. Arenes and amines employed in this study.
6

Table 1. Sequential borylation cross-coupling amination of 2-halopyridines.
Turning to the corresponding isonicotinates (Table 1, entries 13-21) initial attempts were
hampered by inefficient borylation of the corresponding esters 2 and 3 under the “standard”
conditions (~68% conversion compared with >90% for the other substrates). Attributing this
to competitive coordination of the Lewis acidic active catalyst, this could be simply
addressed by increasing the catalyst loading to 5 mol% which enabled conversions in excess
7

of 90% to be routinely achieved. As with the earlier examples, cross-coupling of the resultant
pyridyl boronate esters occurred efficiently. However initial attempts to employ methyl ester
7z in the SNAr step led to the formation of the corresponding amide 13. Two strategies to
circumvent this problem were developed. Simply replacing the methyl ester by a tert-butyl
ester enabled the amino esters to be isolated in moderate yields (Table 1 entries 18-21)
although aromatic amines were still not tolerated (Table 1, entry 20). Alternatively, using the
more reactive 2-fluoropyridine starting material enhanced the facility of the SNAr reaction
enabling lower reaction temperatures to be employed, leading to selective reaction at C-2
even in the presence of the methyl ester (Table 1 entries 13-17).
Figure 3. Structure of amide 13.
Having demonstrated the possibility for multidirectional approaches around a pyridine
template it was of interest to explore other starting pyridine substitution patterns. Retaining a
2-halo substituent, as the borylation enabling (coordination blocking) but labile group, both
2,3- and 2,5-nicotinates were then explored (Table 2). As expected borylation of the 2,5-
isomers 14 and 15 occurred preferentially at the sterically unencumbered C-5 site removed
from the azinyl nitrogen.20-24 However small amounts (6-9%) of the α-azinyl (C-6) boronate
ester could be observed in the crude reaction mixture but underwent rapid protodeborylation
and was not isolable or detectable following the in situ cross coupling reaction. With the 2,3-
isomer 16, similar sterically directed borylation led exclusively to the 3-borylated product.
For this group of compounds use of the smaller 2-fluoro starting material led to a faster
reaction consistent with other observations describing fluorine to act as a C-H activation
enhancing group.25,26,27 In both cases whilst the major boronate esters were isolable, it was
more efficient to carry out a ‘one-pot’ process to afford the corresponding biaryl (17-19) in
acceptable yields following application of the standard cross coupling conditions. As before
SNAr chemistry with a variety of amines proved facile with anilines again requiring the use of
the more reactive fluorine leaving group. With the 2,3 series use of a diamine enabled double
substitution to afford the pyridodiazepinone 23 (Scheme 1a). For these substrates, reflecting
the higher stability of a non α-azinyl boronate ester, the alternative order of events involving
8

initial displacement with the amine and then borylation of the corresponding 2-amino-
pyridine proved to be equally effective (Scheme 1b).
Table 2. Sequential borylation cross-coupling amination of 2-halonicotinates.
Further extension of the levels of diversity possible can be realised through other standard
functional group transformations (Scheme 1). For example, rather than exploit the 2-halo
9

substituent through SNAr chemistry other options exist using further metal catalysed
transformations, with simple reduction using ammonium formate giving ester 25 (Scheme 1c)
or via a second Suzuki-Miyaura reaction, the diarylpyridine 26 (Scheme 1d). Similarly, the
ester substituents can easily be converted to the corresponding acid and hence provides a
simple handle for the introduction of further variation into the reaction sequence (Scheme
1e).
Scheme 1.: Exemplar diversity synthesis of pyridines enabled by C-H borylation.
Conclusion
In this report we have demonstrated that the combination of iridium catalysed C-H borylation
and SNAr chemistry provide a very simple method to elaborate a 2-halopyridine ring and
provide substitution patterns that would be difficult to achieve using traditional heterocycle
synthesis. The functional group tolerant nature of the borylation reaction allows many
10

alternative diverse elements to be incorporated in this sequence with minimal impact on the
chemistry enabled. Given the wide scope for elaboration of the intermediate boronate ester
the potential of the approach to generate diversity extends beyond the examples presented.
Overall this study provides further testimony for the use of C-H borylation as a powerful
means to generating otherwise challenging pyridine, and other heterocycle, substitution
patterns.
Experimental
General Procedure A: Tandem C-H Borylation-Suzuki-Miyaura Cross-Coupling
Sequence:
A solution of [Ir(COD)OMe]2 (5 mol%), dtbpy (5 mol%) and B2pin2 (1.2 mol%) in MTBE
(0.4M) was prepared in a sealed vial and an aliquot then added to a thick-walled microwave
synthesis vial containing the starting pyridine . The vessel was sealed with a crimp top
septum cap and shaken until all of the substrate was dissolved. The reaction mixture was
stirred on a magnetic stirring block or irradiated in a microwave reactor for the stated time
and temperature. Upon completion, the volatiles were removed in vacuo to afford the crude
borylated product.
To the crude mixture under N2, was added palladium catalyst (5 mol%), base (2 equiv.), aryl
halide (1.1 – 2.0 equiv.) and the stated solvent. The reaction was heated at the stated
temperature for the stated time. The reaction mixture was diluted with water and extracted
into EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to
give the crude product. This was dry-loaded onto silica gel and purified by silica gel flash
column chromatography using the stated solvent system.
General Method B SNAr substitution of 2-fluorinated pyridines:
A mixture of the 2-fluorinated pyridine derivatives (1 equiv.), K2CO3 (2 equiv.) and amine (2
equiv.) were heated under reflux in dioxane for 6 h. The reaction was cooled to room
temperature and filtered through Celite. Purification was achieved by flash column
chromatography using EtOAc in hexane.
General method C SNAr substitution of 2-chlorinated pyridines (-CO2Me substituted):
To a sealed, evacuated and N2 backfilled vial containing the 2-chloropyridine derivative,
methanol was added. To this solution, the amine was added and the reaction mixture was
11

o
irradiated in a microwave reactor at 130 C for 30 mins. Following evaporation of volatiles,
the resulting mixture was redissolved in DCM and washed with NaHCO3. Purification
through column chromatography using EtOAc in hexane yielded the title compound.
General Method D SNAr substitution of 2-chlorinated pyridines (non -CO2Me
substituted):
2-Chloropyridine derivatives were transferred to microwave vessel which was then sealed,
evacuated and backfilled with N2. The amine (2 mL) was then added and the reaction mixture
o
was irradiated in a microwave reactor at 130 C for 30 mins. Following the reaction, the
resulting mixture was dissolved in DCM and washed with NaHCO3. Purification was
achieved by flash column chromatography using EtOAc in Hexane.
(5z) 4-Trifluoromethyl-6-chloro-2(4’-nitrophenyl)-pyridine
Following general procedure A and purification using toluene in hexane (0-50%) yielded the
title compound as a white solid (175 mg, 58%). mp 120-121 ºC. δH (700 MHz, CDCl3) 8.36-
8.33 (2H, m, 3’,5’-H), 8.24-8.20 (2H, m, 2’,6’-H), 7.9 (1H, s, 3-H), 7.6 (1H, s, 5- H); δC (176
MHz, CDCl3) 156.9 (C-2), 153.0 (C-6), 149.2 (C-4’), 142.3 (q, J = 34.7 Hz, C-4), 142.1 (C-
1’), 128.2 (C-2’,6’), 124.3 (C-3’,5’), 122.1 (q, J = 274 Hz, CF3), 120.3 (q, J = 3.6 Hz, C-5),
115.4 (q, J = 3.4 Hz, C-3). υmax (ATR) 1601, 1564, 1516, 1409, 1350, 1328, 1263, 1173,
1140, 1101, 1071, 860, 873, 818, 760, 707, 696, 675 cm-1. m/z (GC-MS, EI+) 304 ([M]
(37Cl)]+, 31%), 302 ([M] (35Cl)]+, 100%). Accurate mass (ES+) m/z found [MH]+ 303.0138;
35
C12H7 ClF3N2O2 requires M, 303.0148.
(9zA) 4-Trifluoromethyl-6-(N-pyrrolidin-yl)-2(4’-nitrophenyl)-pyridine
Following general procedure D and purification using EtOAc in hexane (0-8%) yielded the
title compound as a yellow solid (263 mg, 78%). mp 212-213 oC. δH (700 MHz, CDCl3) 8.31-
8.27 (2H, m, 3’,5’-H), 8.22-8.18 (2H, m, 2’,6’-H), 7.19 (1H, s, 3-H), 6.57 (1H, s, 5-H), 3.63-
3.59 (4H, m, 2”,5”-H2), 2.11-2.04 (4H, m, 3”, 4”-H2); δC (176 MHz, CDCl3) 157.16 (C6),
154.3 (C-2), 148.3 (C-4’), 145.1 (C-1’), 140.39 (q, J = 32.9, C-4), 127.7 (C-2’,6’), 123.9 (C-
3’,5’), 123.43 (q, J = 273 Hz, CF3), 103.6 (q, J = 3.3 Hz, C-3), 102.44 (q, J = 4.0 Hz, C-5),
47.1 (C-2”,5”), 25.6 (C-3”,4”); υmax (ATR) 1616, 1601, 1564, 1519, 1492, 1480, 1443, 1390,
1344, 1322, 1290, 1249, 1159, 1108, 1093, 1010, 972, 849, 826, 756, 722, 694, 671 cm-1. m/z
12

(GC-MS, EI+) 337 ([M]+ 39%), 308 ([M-C2H5]+ 100%), Accurate Mass (ESI) m/z found
[M+H]+ 338.1105; C16H15F3N3O2 requires M, 338.1116.
(9zB) 4-Trifluoromethyl-6-(N-morpholin-yl)-2(4’-nitrophenyl)-pyridine
Following general procedure D and purification using EtOAc in hexane (0-12%) yielded the
title compound as a yellow solid (325 mg, 92%). mp 268-269 oC. δH (700 MHz, CDCl3) 8.35-
8.26 (2H, m, 3’,5’-H), 8.23-8.12 (2H, m, 2’,6’-H), 7.33 (1H, s, 3-H), 6.85 (1H, s, 5-H), 3.9-
3.86 (4H, m, 3”,5”-H2), 3.71-3.67 (4H, m, 2”,6”-H2); δC (176 MHz, CDCl3) 159.4 (C-6),
154.4 (C-2), 148.5 (C-4’), 144.6 (C-1’), 141.3 (q, J = 33.0 Hz, C-4), 127 (C-2’, 6’), 124.1 (C-
3’, 5’), 123.2 (q, J = 273 Hz, CF3), 106.1 (q, J = 3.3 Hz, C-3), 102.6 (q, J = 4.0 Hz, C-5), 66.7
(C-3”,5”), 45.4 (C-2”,6”). υmax (ATR) 1603, 1567, 1517, 1438, 1324, 1302, 1242, 1161,
1111, 982, 967, 847, 825, 757, 711, 695, 675 cm-1. m/z (GC-MS, EI+) (353 [M]+), 68%, (334
[M-F]+, 17%), 308 ([MH-NO2]+, 24%). Accurate Mass (ESI) m/z found [M+H]+ 354.1067;
C16H15F3N3O3 requires M, 354.1066.
(9zD) Diethyl-[6-(4’-nitrophenyl)-4-trifluoromethylpyridine-2-yl]amine
Following general procedure D, and purification using EtOAc in hexane (0-8%) yielded
o
the title compound as a yellow solid (207 mg, 61%). mp 88-89 C. δH (700 MHz,
CDCl3) 8.32-8.27 (2H, m, 3’,5’-H), 8.21-8.15 (2H, m, 2’,6’-H), 7.20 (1H, s, 3-H), 6.7
(1H, s, 5-H), 3.63-3.59 (4H, q, J = 7.1 Hz, 2”,4”-H2), 1.26 (6H, t, J = 7.1 Hz, 3”,5”-H3);
δC (176 MHz, CDCl3) 157.5 (C-6), 154.3 (C-2), 148.3 (C-4’), 145.2 (C-1’), 140.7 (q, J =
32.7, C-4), 127.6 (C-2’,6’), 124.0 (C-3’,5’), 123.4 (q, J = 273 Hz, CF3), 103.5 (q, J = 3.3
Hz, C-3), 101.4 (q, J = 4.0 Hz, C-5), 43.13 (C-2”,4”), 12.9 (C-3”,5”). υmax (ATR) 1616,
1601, 1566, 1516, 1503, 1442, 1349, 1344, 1332, 1263, 1249, 1175, 1123, 1110, 979,
853, 829, 758, 710, 695, 676 cm-1. m/z (GC-MS, EI+) 339 ([M]+, 43%), 324 ([M-CH3]+,
64%), 310 ([M-C2H5]+, 100%). Accurate Mass (ESI) m/z found [M+H]+ 340.1270;
C16H17F3N3O2 requires M, 340.1273.
(9zE) Butyl-[6-(4’-nitrophenyl)-4-trifluoromethylpyridine-2-yl]amine
Following general procedure D, and purification using EtOAc in hexane (0-8%) yielded
o
the title compound as a yellow solid (255 mg, 75%), mp = 163-164 C. δH (700 MHz,
CDCl3) 8.31-8.26 (2H, m, 3’,5’-H), 8.18-8.11 (2H, m, 2’,6’-H), 7.2 (1H, d, J = 0.6 Hz,
3-H), 6.6 (1H, s, 5-H), 4.9 (1H, s broad, NH), 3.44-3.39 (2H, m, 1”-H2), 1.69-1.64 (2H,
m, 2”-H2), 1.51.44 (2H, m, 3”-H2), 1.0 (3H, t, J = 7.4 Hz, 4”-H3); δC (176 MHz, CDCl3)
13

159.1 (C-6), 154.7 (C-2’), 148.4 (C-4’), 144.7 (C-1’), 140.8 (q, J = 33.2 Hz, C-4), 127.7
(C-2’,6’), 124.0 (C3’,5’), 123.2 (q, J = 273 Hz, CF3), 105.3 (q, J = 3.3 Hz, C-3), 102.8
(C-5), 42.0 (C-2”), 31.6 (C-3”), 20.3 (C-4”), 14.0 (C-5”). υmax (ATR) 3401 (NH), 1625,
1604, 1573, 1533, 1459, 1413, 1396, 1331, 1257, 1158, 1117, 1096, 860, 830, 757, 723,
695, 678, 639 cm-1. m/z (GC-MS, EI+) 339 ([M]+, 31%), 310 ([M-C2H5]+, 52%), 296
([M-C3H7]+, 100%). Accurate Mass (ESI) m/z found [M+H]+ 340.1276; C16H17F3N3O2
requires M, 340.1273.
(5y) 4-Trifluoromethyl-6-chloro-2-(4’-methoxyphenyl)-pyridine
Following general procedure A, and purification using Et2O in hexane (0-5%) yielded
the title compound as a yellow oil (105 mg, 36%). δH (700 MHz, CDCl3) 7.99-7.94 (2H,
m, 2’,6’-H), 7.73 (1H, d, J = 0.6 Hz, 3-H), 7.37 (1H, d, J = 0.6 Hz, 5-H), 6.99-6.94 (2H,
m, 3’,5’-H), 3.85 (3H, s, OCH3); δC (176 MHz, CDCl3) 161.7 (C-4’), 159.1 (C-2), 151.2
(C-6), 141.5 (q, J = 34.1 Hz, C-4), 129.0 (C-1’), 128.6 (C-2’,6’), 122.4 (q, J = 273 Hz,
CF3), 117.0 (q, J = 3.7 Hz, C-5), 114.4 (C-3’,5’), 113.4 (q, J = 3.7 Hz, C-3), 55.4 (O-
CH3). υmax (ATR) 1606, 1557, 1518, 1408, 1394, 1331, 1265, 1253, 1175, 1135, 1098,
1072, 1031, 830, 694, 665, 581 cm-1. m/z (GC-MS, EI+) 289 [M (37Cl)]+, 33%, 287 ([M
(35Cl)]+, 100%). Accurate mass (ES+) m/z found [MH]+ 288.0401; C13H1035ClF3NO
requires M, 288.0403.
(9yA) 4-Trifluoromethyl-6-(N-pyrrolidin-yl)-2-(4’-methoxyphenyl)pyridine
Following general procedure D, the crude mixture of 4-trifluoromethyl-6-chloro-2-
(4’methoxyphenyl)-pyridine in (~1.0 mmol) and pyrrolidine (0.46 mL, 5.5 mmol) were
combined at 130 oC for 30 min. Purification through flash chromatography using EtOAc
in hexane (0-5%) yielded the title compound as an off white solid (65 mg, 20% (over 3
steps)). mp 103-104 oC. δH (700 MHz, CDCl3) 8.06-8.00 (2H, m, 2’, 6’-H), 7.11 (1H, s,
3H), 7.01-6.96 (2H, m, 3’,5’-H), 6.42 (1H, s, 5-H), 3.86 (3H, s, OCH3), 3.64-3.53 (4H,
m, 2”,5”-H2), 2.08-2.00 (4H, m, 3”,4”-H2); δC (176 MHz, CDCl3) 160.7 (C-4’), 157.0
(C-6), 156.6 (C-2), 140.0 ( q, J = 32.4 Hz, C-4), 132.0 (C-1’), 128.3 (C-2’,6’), 123.77
(q, J = 273 Hz, CF3), 114.0 (C-3’,5’), 102.1 (q, J = 3.4 Hz, C-3), 100.0 (q, J = 4.0 Hz,
C-5), 55.4 (O-CH3), 46.9 (C-2”,5”), 25.6 (C-3”,4”). υmax (ATR) 1613, 1563, 1497, 1460
1439, 1408, 1389, 1351, 1333, 1304, 1293,1246, 1183, 1157, 1120, 1105, 1097, 1051,
1032, 1014, 1004, 842, 825, 804, 782, 711, 680, 671, 648, 637, 618, 586, 522, 504 cm-1.
14

m/z (GC-MS, EI+) 323 [MH]+, 7%, 322 [M]+, 42%, 293 [MHOCH3]+, 100%; Accurate
Mass (ESI) m/z found [M+H]+ 323.1364; C17H18F3N2O requires M, 323.1371.
(5w) 2-Chloro-4-(trifluoromethyl)-6-(3’-methoxyphenyl)pyridine
Following general procedure A, and purification using Et2O in heptane (0-3%) yielded
the title compound as an off-white amorphous solid (147 mg, 51%). δH (700 MHz,
CDCl3) 7.83 (1H, s, 5-H), 7.59 (1H, t, J = 2.3, 2’-H), 7.58 (1H, d, J = 7.9, 6’-H), 7.48
(1H, s, 3-H), 7.41 (1H, t, J = 7.9, 5’-H), 7.03 (1H, dd, J = 7.9, 2.3, 4’-H), 3.91 (3H, s,
OCH3); δC (176 MHz, CDCl3) 160.4 (C-3’), 159.4 (C-6), 152.4 (C-2), 141.8 (q, J =
34.3, C-4), 138.0 (C-1’), 130.2 (C-5’), 122.3 (q, J = 274.0, CF3), 119.6 (C-6’), 118.7 (q,
J = 3.7, C-3), 116.6 (C-4’), 114.8 (q, J = 3.5, C-5), 112.6 (C-2’), 55.6 (OCH3); δF (376
MHz, CDCl3) −64.7 (s); νmax (ATR) 1600, 1561, 1459, 1400, 1333, 1274, 1221, 1177,
35
1142, 1102 cm−1; Accurate Mass (ASAP) m/z found [M]+ 287.0330; C13H9 ClF3NO
requires M, 287.0325.
(6z) 4-tert-Butyl-6-chloro-2-(4’-nitrophenyl)pyridine
Following general procedure A and purification using EtOAc in hexane (0-6%) yielded the
o
title compound as an off white solid (117 mg, 40%). mp 192-193 C. δH (700 MHz, CDCl3)
8.33-8.27 (2H, m, 3’,5’-H) 8.19-8.12 (2H, m, 2’,6’-H), 7.69 (1H, d, J = 1.5 Hz, 3-H), 7.34
(1H, d, J = 1.5 Hz, 5-H), 1.38 (9H, s, 4-C(CH3)3); δC (176 MHz, CDCl3) 164.8 (C-4), 155.3
(C-2), 152.3 (C-6), 148.5 (C-4’), 144.3 (C-1’), 128.0 (C-2’,6’), 124.1 (C-3’,5’), 121.4 (C-5),
117.2 (C-3), 35.5 (4-C), 30.6 (CH3) υmax (ATR), 1588, 1533, 1509, 1410, 1338, 1171, 1104,
856, 813, 762, 731, 698, 644 cm-1. Accurate mass (ES+) m/z found [MH]+ 291.0904;
C15H1635ClN2O2 requires M, 291.0900.
(10zA) 4-tert-Butyl-6-(N-pyrrolidinyl)-2-(4’-nitrophenyl)pyridine
Following general procedure D and purification using EtOAc in hexane (0-8%) yielded
o
the title compound as a red solid (100 mg, 31%), mp 180.5-182.5 C. δH (700 MHz,
CDCl3) 8.3-8.23 (2H, m, 3’,5’-H), 8.21-8.17 (2H, m, 2’,6’-H), 7.09 (1H, d, J = 1.3 Hz,
3-H), 6.38 (1H, d, J = 1.3 Hz, 5-H), 3.55-3.60 (4H, m, 2”,5”-H2), 2.06-2.01 (4H, m,
3”,4”-H2), 1.35 (9H, s, CH3); δC (176 MHz, CDCl3) 161.9 (C4),157.7 (C-6), 152.6 (C-
2), 147.7 (C-4’), 146.9 (C-4’), 127.6 (C-2’,6’), 123.8 (C-3’,5’), 107.03 (C-3), 103.4 (C-
5), 47.0 (C-2”,5”), 35.12 (4-C), 30.8 (4-C-(CH3)3)), 25.7 (C-3˶, 4˶). υmax (ATR) 1597,
1549, 1501, 1476, 1456, 1323, 1107, 1101, 1011, 865, 850, 842, 832, 760, 698, 659,
15

631, 495 cm-1; m/z (GC-MS, EI+) 326 ([MH]+, 16%), 325 ([M]+, 78%). Accurate Mass
(ESI) m/z found [M+H]+ 326.1869; C19H24N3O2 requires M, 326.1869.
(6y) 4-tert-Butyl-6-chloro-2-(4’-methoxyphenyl)pyridine
Following general procedure A and purification using Et2O in hexane (0-5%) yielded the title
compound as a colourless oil (121 mg, 44%). δH (700 MHz, CDCl3) 7.96-7.92 (2H, m, 2’, 6’-
H), 7.55 (1H, d, J = 1.5 Hz, 3-H), 7.18 (1H, d, J = 1.5 Hz, 5-H), 7.00-6.95 (2H, m, 3’,5’-H),
3.86 (3H, s, OCH3), 1.35 (9H, s, 4-C(CH3)3); δC (176 MHz, CDCl3) 164.0 (C-4), 160.9 (C-
4’), 157.7 (C-2), 151.6 (C-6), 131.0 (C-1’), 128.5 (C-2’, 6’), 119.0 (C-5), 115.5 (C3), 114.2
(C-3’, 5’), 55.5 (OCH3), 36.3 (4-C), 30.6 (CH3). υmax (ATR) 1607, 1591, 1535, 1514, 1462,
1410, 1385, 1303, 1247, 1175, 1111, 1074, 1031, 878, 831, 780, 650, 585, 507 cm-1. m/z
(GC-MS, EI+) 277 ([M (37Cl)]+ , 31%), 275 ([M ( 35Cl)]+, 100%). Accurate mass (ES+) m/z
found [MH]+ 276.1159; C16H1935ClNO requires M, 276.1155.
(6v) 4-tert-Butyl-6-chloro-2-(3’-thiophenyl) pyridine
Following general procedure A and purification using EtOAc in hexane (0-7%) yielded the
o
title compound as a white solid (168 mg, 67%). mp 50-51 C. δH (700 MHz, CDCl3) 8.95
(1H, dd, J = 3.0, 1.3 Hz, 2’-H), 7.6 (1H, dd, J = 5.0, 1.3 Hz, 4’-H), 7.5 (1H, d, J = 1.5 Hz, 3-
H), 7.3 (1H, dd, J = 5.0, 3.0 Hz, 5’-H), 7.18 (1H, d, J = 1.5 Hz, 5-H), 1.35 (9H, s, CH3); δC
(176 MHz, CDCl3) 164.2 (C-4), 153.9 (C-2), 151.6 (C-6), 141.2 (C-3’), 126.5 (C-5’), 126.3
(C-4’), 124.5 (C-2’), 119.4 (C-5), 116.1 (C-3), 35.3 (4-C), 30.6 (CH3). υmax (ATR) 1591,
1540, 1477, 1434, 1422, 1362, 1346, 1287, 1200, 1165, 1079, 1062, 861, 831, 794, 774, 731,
671 cm-1. Accurate mass (ES+) m/z found [MH]+ 252.0596; C13H1535ClNS requires M,
252.0614.
(6u) 4-tert-Butyl-6-chloro-2-(2’-thiazolyl)pyridine
Following general procedure A and purification using EtOAc in hexane (0-10%) yielded the
title compound as an off white solid (106 mg, 42%). mp. 96.5-97.5 oC. δH (700 MHz, CDCl3)
8.12 (1H, d, J = 1.5 Hz, 3-H) 7.9 (1H, d, J = 3.1 Hz, 5’-H), 7.5 (1H, d, J = 3.1 Hz, 4’-H), 7.3
(1H, d, J = 1.5 Hz, 5-H), 1.36 (9H, s, CH3); δC (176 MHz, CDCl3) 168.2 (C-2’), 165.0 (C-4),
151.6 (C-2), 151.4 (C-6), 144.1 (C-5’), 122.2 (C-5), 122.0 (C-4’), 115.6 (C-3), 35.5 (4-C),
30.6 (CH3). υmax (ATR) 1591, 1541, 1500, 1478, 1440, 1381, 1242, 1168, 1151, 1048, 874,
863, 794, 770, 745, 723, 620, 583, 515 cm-1. m/z (GC-MS, EI+) 254 ([M (37Cl)]+, 24%), 252
16

([M (35Cl)]+, 65%). Accurate mass (ES+) m/z found [MH]+ 253.0584; C12H1535ClN2S requires
M, 253.0566.
(6t) 4-tert-Butyl-6-chloro-2,2’-bipyridinyl-4’-carboxylic acid methyl ester
Following general procedure A and purification using EtOAc in chloroform (0-5%) yielded
o
the title compound as a white solid (200 mg, 66%). mp. 103-104 C. δH (600 MHz, CDCl3)
8.9 (1H, bs, 3’-H) 8.8 (1H, d, J = 5.0 Hz, 6’-H), 8.4 (1H, d, J = 1.6 Hz, 3-H), 7.86 (1H, dd, J
= 5.0, 1.6 Hz, 5’-H), 7.3 (1H, d, J = 1.6 Hz, 5-H), 4.0 (3H, s, OCH3), 1.38 (9H, s, C(CH3)3);
δC (151 MHz, CDCl3) 165.8 (C=O), 164.7 (C-4), 156.3 (C-2’), 155.7 (C-2), 151.5 (C-6),
150.0 (C-6’), 138.7 (C-4’), 123.3 (C-5’), 122.0 (C-5), 121.0 (C-3’), 117.2 (C-3), 52.8
(OCH3), 35.5 (4-C), 30.6 (CCH3). υmax (ATR), 1726 (C=O), 1585, 1532, 1478, 1438, 1373,
1365, 1356, 1315, 1294, 1268, 1165, 1133, 1100, 966, 891, 859, 769, 751, 694, 674, 650 cm-
1. m/z (GC-MS, EI+) 306 ([M(37Cl)]+, 8%), 304 ([M (35Cl)]+, 25%), 291 ([M (37Cl)-CH3]+,
37%), 289 ([M (35Cl)-CH3]+, 100%). Accurate mass (ES+) m/z found [MH]+ 305.1065;
C16H1735ClN2O2 requires M, 305.1057.
(7z) Methyl-6-chloro-2-(4’-nitrophenyl)pyridine-4-carboxylate
Following general procedure A and purification using DCM in toluene (0-30%) yielded the
title compound as a yellow solid (130 mg, 45%), mp 166-167 oC. δH (700 MHz, CDCl3) 8.36-
8.33 (2H, m, 3’,5’-H), 8.3 (1H, d, J = 1.1 Hz, 3-H), 8.3-8.23 (2H, m, 2’,6’-H), 7.9 (1H, d, J =
1.1 Hz, 5-H), 4.0 (3H, s, OCH3). δC (176 MHz, CDCl3) 164.3 (C=O), 156.9 (C-2), 152.9 (C-
6), 149.0 (C-4’), 142.8 (C1’), 141.5 (C-4), 128.1 (C-2’,6’), 124.3 (C-3’,5’), 123.8 (C-3),
119.0 (C-5), 53.4 (OCH3). υmax (ATR) 1733 (C=O), 1591, 1557, 1514, 1439, 1404, 1340,
1317, 1252, 1244, 1156, 1104, 982, 857, 818, 770, 755, 742, 722, 689 cm-1; m/z (GC-MS,
EI+) 294 ([M (37Cl)]+, 33%), 292 ([M (35Cl)]+, 100%). Accurate mass (ES+) m/z found [MH]+
293.0344; C13H1035ClN2O4 requires M, 293.0329.
(7y) Methyl-6-chloro-2-(4’-methoxyphenyl)-pyridine-4-carboxylate
Following general procedure A and purification using EtOAc in hexane (0-10%) yielded the
o
title compound as a white solid (134.5 mg, 48%). mp. 102-103 C. δH (700 MHz, CDCl3)
8.11 (1H, d, J = 1.2 Hz, 3- H), 8.03-7.96 (2H, m, 2’,6’-H), 7.7 (1H, d, J = 1.2 Hz, 5-H), 7.01-
6.93 (2H, m, 3’,5’-H), 4.0 (3H, s, CO2CH3), 3.86 (3H, s, 4’-OCH3); δC (176 MHz, CDCl3)
164.8 (C=O), 161.4 (C-4’), 158.7 (C-2), 152.0 (C-6), 140.8 (C-4), 129.6 (C-1’), 128.6 (C-
17

2’,6’), 121.1 (C-5), 117.3 (C3), 114.4 (C-3’,5’), 55.5 (4’-OCH3), 53.1 (CO2CH3) υmax (ATR)
1734 (C=O), 1606, 1597, 1583, 1549, 1519, 1441, 1404, 1390, 1302, 1256, 1180, 1161,
1113, 1071, 1021, 981, 824, 761, 732, 615, 585 cm-1. m/z (GC-MS, EI+) 279 ([M (37Cl)]+,
32%), 277 ([M (35Cl)]+, 100%). Accurate mass (ES+) m/z found [MH]+ 278.0600;
C14H1335ClNO3 requires M, 278.0584.
(7’y) Methyl 2-fluoro-6-(4’-methoxyphenyl)pyridine-4-carboxylate
Following general procedure A and purification using EtOAc in hexanes (0-20%) yielded the
title compound as a colourless oil (157 mg, 55%). δH (700 MHz, CDCl3) 8.13 (1H, m, 5-H),
8.03 (2H, m, 2’, 6’-H), 7.32 (1H, m, 3-H), 7.00 (2H, m, 3’, 5’-H), 4.00 (3H, s, CO2CH3), 3.88
(3H, s, COCH3); δC (176 MHz, CDCl3) 164.8 (d, J = 4.2, CO2CH3), 162.3 (d, J = 247.0, C-2),
161.5 (C-4’), 157.2 (d, J = 14.0, C-6), 143.4 (d, J = 8.0, C-4), 129.5 (C-1’), 128.6 (C-2’, 6’),
116.3 (d, J = 5.0, C-5), 114.4 (C-3’, 5’), 106.7 (d, J = 40.0 Hz, C-3), 55.6 (CO2CH3), 53.1
(OCH3); δF (376 MHz, CDCl3) -66.2 (s); νmax (ATR) 1733, 1608, 1568, 1520, 1420, 1396,
1352, 1252, 1206 1177 cm−1; GC/MS (EI) m/z 261 [M]+, 246 [M−CH3]+, 230 [M−OCH3].
Accurate Mass (ASAP) m/z found [M]+ 261.0811; C14H12FNO3 requires M, 261.0801.
(11yA) Methyl 2-(4’-methoxyphenyl)-6-(pyrrolidin-1”-yl)pyridine-4-carboxylate
Following general procedure B and purification using EtOAc in hexane (0-15%) yielded the
title compound as a white amorphous solid (32 mg 85%) δH (600 MHz, CDCl3) 8.02 (2H, d, J
= 8.8 Hz, 2’, 6’-H), 7.46 (1H, d, J = 1.2 Hz, 3-H), 6.95 (2H, d, J = 8.8 Hz, 3’, 5’-H), 6.83
(1H. d, J = 1.2 Hz, 5-H), 3.93 (3H, s, CO2CH3), 3.84 (3H, s, 4’-OCH3), 3.54-3.62 (4H, m,
2’’,5’’-H2), 2.11 – 1.92 (4H, m, 3’’H, 4’’-H2). δC (151 MHz, CDCl3) 166.86 (C=O), 161.08
(C-4’), 157.22 (C-2), 156.11 (C-2), 155.8 (C-6), 132.1 (C-1’), 139.08 (C-4), 128.1 (C-2’, 6’),
113.8 (C-3’, 5’), 105.8 (C-3), 104.2 (C-5), 55.31 (4’-OCH3), 52.36 (CO2CH3), 46.9 (C-2’’,
5’’), 25.5 (C-3’’, 4’’). νmax (ATR) 2949, 2848, 1719, 1611, 1554, 1444, 1243, 1030, 1178,
766 cm-1. GC/MS (EI) m/z 313.1 [M+H]+ (100%). Accurate Mass (ES+) m/z found [M+H]+
313.1562, C18H21N2O3 requires M, 313.1552.
(7’x) Methyl 2-fluoro-6-(4’-trifluoromethylphenyl) pyridine-4-carboxylate
Following general procedure A and purification using C18 reverse phase chromatography
(H2O: MeCN, 0-100%) to yield the title compound as a white amorphous solid (151 mg,
50%). δH (700 MHz, CDCl3) 8.22 (1H, dd, J = 2.0, 0.8 Hz, 5-H), 8.15 (2H, d, J = 8.4, 2’,6’-
18

H), 7.74 (2H, d, J = 8.4, 3’,5’-H), 7.46 (1H. dd, 0.8, 0.4 Hz, 3-H), 4.01 (3H, s, -OCH3). δC
(176 MHz, CDCl3) 164.3 (d, J = 4.1 Hz C=O), 163.8 (d, J = 241.1 Hz, C-2), 155.5 (d, J =
14.0 Hz, C-6) 143.7 (d, J = 6.9 Hz, C-4), 139.92 (C-1’), 131.8 (q, J = 32.2 Hz, C-6’), 127.3
(C-2’, 6’), 125.8 (C-3’, 5’), 124.0 (q, J = 263.3 Hz, -CF3), 117.3 (d, J = 4.7 Hz C-5), 108.8 (d,
J = 39.7 Hz, C-3) 53.1 (-OCH3). δF (376 MHz, CDCl3) -62.78 (-CF3), -65.15 (Ar-F). νmax
(ATR) 2957, 2256, 1741, 1578, 1329, 1255, 1136, 905, 731 cm-1. GC/MS (EI) m/z found
[M+H]+ 300.0, [M+MeCN+H]+ 341.1. Accurate Mass (ES+) m/z found [M+H]+ 300.0670,
C14H10F4NO2 requires M 300.0648.
(11xB) Methyl 2-(morpholin-4”-yl)-6-[4’-(trifluoromethyl)phenyl]pyridine-4-carboxylate
Following general procedure B and purification using EtOAc in hexane (0-15%) yielded the
title compound as an off white solid (28 mg, 83%). mp. 272-273 oC (ethanol). δH (599 MHz,
CDCl3) 8.14 (2H, d, J = 8.3 Hz, 3’, 5’-H), 7.70 (2H, d, J = 8.3 Hz, 2’, 6’-H), 7.69 (1H, d, J =
1.0 Hz, 3-H), 7.25 (1H, d, J = 1.0 Hz, 5-H), 3.97 (3H, s, -OCH3), 3.90 – 3.83 (2H, m, 3’’, 5’’-
H2), 3.71 – 3.64 (1H, m, 2’’, 6’’-H2). δC (151 MHz, CDCl3) 166.1 (C=O), 159.54 (C-2),
154.6 (C-4), 142.3 (C-6), 140.0 (C-1’), 130.9 (q, J = 30.7 Hz, C-4’) 127.1 (C-2’’, 6’’), 125.5
(q, J = 4.0 Hz C-3’’, 5’’), 124.2 (q, J = 271.0 Hz -CF3), 109.42 (C-3), 106.1 (C-5), 66.7 (C-
3’’, 5’’), 52.6 (-OCH3), 45.5 (C-2’’, 6’’). δF (376 MHz, CDCl3) -62.56. νmax (ATR) 2960,
2860, 2259, 1734, 1604, 1563, 1444, 1237, 1124 cm-1. GC/MS (EI) m/z found [M+H]+ 367.1.
Accurate Mass (ES+) m/z found [M+H]+ 367.1279, C18H18F3N2O3 requires M 367.1270.
(11xE) Methyl 2-(butylamino)-6-[4’-(trifluoromethyl)phenyl]pyridine-4-carboxylate
Following general procedure B and purification using EtOAc in hexane (0-40%) yielded the
title compound as a light yellow oil (36 mg, 64%). δH (700 MHz, CDCl3) 8.10 (1H, d, J = 7.6
Hz, 2’, 6’-H), 7.71 (2H, d, J = 7.6 Hz, 3’, 5’H), 7.55 (1H, d, J = 1.1 Hz, 3-H), 6.98 (1H, d, J
= 1.1 Hz, 5-H), 3.95 (3H, s, -OCH3), 3.39 (2H, q, J = 6.7 Hz, 1’’-H2), 1.70 – 1.62 (2H, m,
2’’-H2), 1.46 (1H, m, 3’’-H2), 0.97 (3H, t, J = 7.4 Hz, 4’’-CH3). δC (176 MHz, CDCl3) 166.1
(C=O), 166.0 (C-2), 158.98 (C-6), 154.3 (C-4) 140.0 (C-1’), 130.8 (q, J = 30.8 Hz, C-4’)
127.1 (C-2’, 6’) , 125.5 (q, J = 3.8 Hz, C-3’, 5’), 124.1 (q, J = 272.0 Hz -CF3), 108.6 (C-3),
106.1 (C-5), 52.6 (-OCH3), 42.0 (C-1’’), 31.5 (C-2’’), 20.2 (C-3’’), 13.8 (C-4’’). δF (376
MHz, CDCl3) -62.58 (-CF3). νmax (ATR) 3423, 2960, 2259, 1724, 1571, 1329, 1249, 1124 cm-
1. GC/MS (EI) m/z found [M+H]+ 353.5. Accurate Mass (ES+) m/z found [M+H]+ 353.1484,
C18H20F3N2O2 requires M 353.1477.
19

(8z) tert-Butyl 2-chloro-6-(4’-nitrophenyl)pyridine-4-carboxylate
Following general procedure A and purification using CHCl3 in hexane (0-60%) yielded the
o
title compound as a bright yellow solid (203 mg, 61%). mp 141-142 C (methanol). δH (599
MHz, CDCl3) 8.32 (2H, d, J = 8.9 Hz, 3’,5’-H), 8.23 – 8.19 (3H, m, 2’,6’, 5-H), 7.81 (1H, d,
J = 1.1 Hz, 3-H), 1.62 (9H, s, OC(CH3)3). δC (151 MHz, CDCl3) 162.5 (C=O), 156.0 (C-6),
152.5 (C-2), 148.7 (C-4’), 143.32 (C-4), 142.8 (C-1’), 127.9 (C-2’, 6’), 124.1 (C-3’, 5’),
123.6 (C-3), 118.9 (C-5), 83.7 (OC(CH3)3), 28.0 ((CH3)3). νmax (ATR) 2984, 1719, 1593,
1548, 1524, 1346, 1160, 861 cm-1. GC/MS (EI) m/z found 325.3 ([M (35Cl)+H]+ 100%),
327.3 ([M (37Cl)+H]+ 31%). Accurate Mass (ES+) m/z found [M (35Cl)+H]+ 335.0803 , [M-
tBu+H]+ 279.0191, C16H1635ClN2O4 requires M 335.0799.
(12zB) tert-Butyl 2-(morpholin-4”-yl)-6-(4’-nitrophenyl)pyridine-4-carboxylate
Following general procedure D and purification using EtOAc in hexane (0-15%) yielded the
o
title compound as a bright yellow solid (27 mg, 78%). mp 216-217 C (ethanol). δH (600
MHz, CDCl3) 8.30 (2H, d, J = 8.9 Hz, 3’, 5’-H), 8.19 (2H, d, J = 8.9 Hz, 2’, 6’-H), 7.66 (1H,
d, J = 1.0 Hz, 3-H), 7.24 (1H, d, J = 1.0 Hz, 5-H), 3.88 (4H, t, J = 4.9 Hz, 3’’, 5’’-H2), 3.69
(4H, t, J = 4.9 Hz, 2’’, 6’’-H2), 1.63 (9H, s, -(CH3)3). δC (151 MHz, CDCl3) 164.4 (C=O) ,
159.5 (C-2), 153.3 (C-4’), 148.1 (C-1’), 145.0 (C-6), 142.1 (C-4), 127.6 (C-2’, 6’), 123.8 (C-
3’, 5’), 110.0 (C-3), 106.8 (C-5), 82.6 (-C(CH3)3), 66.6 (C-3’’, 5’’), 45.6 (C-2’’, 6’’), 28.1 (-
(CH3)3). νmax (ATR) 2982, 2863, 1717, 1596, 1563, 1516, 1433, 1341, 1251, 998 cm-1.
GC/MS (EI) m/z found 386.1 ([M+H]+ 100%), 330.1 ([M-tBu+H]+ 62%). Accurate Mass
(ES+) m/z found [M+H]+ 386.1726, C20H24N3O5 requires M 386.1716.
(8y) tert-Butyl 2-chloro-6-(4’-methoxyphenyl)pyridine-4-carboxylate
Following general procedure A and purification using CHCl3 in hexane (0-55%) yielded the
o
title compound as an off white solid (182 mg, 57%). mp, 119-120 C (methanol). δH (600
MHz, CDCl3) 8.07 (1H, d, J = 1.2 Hz, 3-H), 8.01 – 7.96 (2H, m, 2’, 6’-H), 7.63 (1H, d, J =
1.1 Hz, 5-H), 7.01 – 6.95 (2H, m, 3’,5’-H), 3.85 (3H, s, -OCH3), 1.61 (9H, s, -(CH3)3). δC
(151 MHz, CDCl3)163.2 (C=O), 161.2 (C-4’), 158.4 (C-6), 151.8 (C-2), 142.7 (C-4), 129.7
(C-1’), 128.5 (C-5), 121.0 (C-2’, 6’), 117.3 (C-3), 114.22 (C-3’ 5’), 83.01 (-C(CH3)3, 55.37 (-
OCH3), 28.0 (OC(CH3)3). νmax (ATR) 2986, 2874, 1728, 1595, 1548, 1415, 1323, 1238, 1147,
1027 cm-1. GC/MS (EI) m/z found 320.6 ([M(35Cl)+H]+ 72%), 322.5 ([M(37Cl)+H]+ 21%).
20

35
Accurate Mass (ES+) m/z found [M(35Cl)+H]+ 320.1071, C17H19NO3 Cl requires M
320.1053.
(12yA) tert-Butyl 2-(4’-methoxyphenyl)-6-(pyrrolidin”-yl)pyridine-4-carboxylate
Following general procedure D and purification using EtOAC in hexane (0-20%) yielded the
title compound as an off white amorphous solid (41 mg, 90%). δH (600 MHz, CDCl3) 8.01
(2H, d, J = 8.7 Hz, 2’, 6’-H), 7.40 (1H, d, J = 1.1 Hz, 3-H), 6.98 (2H, d, J = 8.7 Hz, 3’, 5’-H),
6.82 (1H, d, J = 1.1 Hz, 5-H), 3.86 (3H, s, -OCH3), 3.57-3.63 (4H, m, 3’’, 4’’-H2), 2.13 –
1.93 (4H, m, 2’’,5’’-H2), 1.61 (9H, s, -(CH3)3). δC (151 MHz, CDC3) 165.4 (C=O), 160.3 (C-
4’), 155.5 (C-2) 141.0 (C-6), 128.2 (C-2’,6’), 124.6 (C-1’), 121.6 (C-4), 113.8 (C-3’,5’),
106.0 (C-3), 104.2 (C-5), 81.7 (-C(CH3)3), 55.3 (-OCH3), 47.0 (C-2’’,5’’), 28.1 (C(CH3)3),
25.5 (C-3’’,4’’). νmax (ATR) 2972, 2859, 1714, 1607, 1557, 1459, 1382, 1246, 1030 cm-1.
GC/MS (EI) m/z found 356.3 ([M+H]+ 100%), Accurate Mass (ES+) m/z found ([M+H]+
355.2022, C21H27N2O3 requires M 355.2022.
(8x) tert-Butyl 2-chloro-6-(4-trifluromethy-lphenyl)pyridine-4-carboxylate
Following general procedure A and purification using C18 reverse phase chromatography
(H2O: MeCN, 0-100%) yielded the title compound as a light brown amorphous solid (140
mg, 39%). δH (700 MHz, CDCl3) 8.19 (1H, d, J = 1.1 Hz, 3-H), 8.18 – 8.15 (2H, d, J = 1, 2’,
6’-H), 7.79 (1H, d, J = 1.1 Hz, 5-H), 7.74 (2H, d, J = 8.1 Hz m, 3’, 5’-H), 1.63 (9H, s, -
(CH3)3). δC (176 MHz, CDCl3) 162.7 (C=O), 157.0 (C-2), 152.3 (C-1’), 143.1 (C-4), 140.4
(C-6), 127.4 (C-2’, 6’), 125.8 (q, J = 3.9 Hz, C-3’, 5’), 123.9 (q, J = 272.2 Hz, -CF3), 123.0
(C-5), 118.5 (C-3), 83.4 (-C(CH3)3), 28.0 (-(CH3)3). δF (376 MHz, CDCl3) -62.72 (-CF3).
νmax (ATR) 2975, 2887, 1726, 1557, 1471, 1382, 1326, 1261, 1131, 950 cm-1. GC/MS (EI)
m/z found 358.1 ([M(35Cl)+H]+ 100%), 360.1 ([M(37Cl)+H]+ 39%). Accurate Mass (ES+) m/z
found [M(35Cl)+H]+ 358.0826, [M(35Cl)-tBu+H]+ 302.0210, C17H1635ClF3NO2 requires M
358.0822.
(12xA) tert-Butyl 2-(pyrrolidin-1-yl)-6-[4-(trifluoromethyl)phenyl]pyridine-4-carboxylate
Following general procedure D and purification using EtOAC in hexane (0-10%) yielded the
o
title compound as a white solid (39 mg, 90%). mp 168-169 C (ethanol). δH (600 MHz,
CDCl3) 8.19 – 8.15 (2H, d, J = 8.2 Hz, 2’, 6’-H), 7.69 (2H, d, J = 8.2 Hz, 3’, 5’-H), 7.48 (1H,
d, J = 1.1 Hz, 3-H), 6.92 (1H, d, J = 1.1 Hz, 5-H), 3.62-3.58 (4H, m, 2’’, 5’’-H), 2.02-2.07
21

(4H, m, 3’, 4’H), 1.62 (9H, s, -(CH3)3). δC (151 MHz, CDCl3) 165.1 (C=O), 157.36 (C-2),
154.32 (C-6), 142.81 (C-4), 141.2 (C-1’), 130.4 (q, J = 32.6 Hz C-4), 127.1 (C-2’,6’), 125.3
(q, J = 3.8 Hz C-3’, 5’), 124.3 (q, J = 273.4 Hz, -CF3), 107.0 (C-3), 106.0 (C-5), 82.0 (-
C(CH3)3), 46.9 (C-2’’, 5’’, 28.1 (-(CH3)3), 25.5 (C-3’’, 4’’). δF (376 MHz, CDCl3) -62.49 (-CF3).
νmax (ATR) 2972, 2839, 2259, 1734, 1604, 1566, 1443, 1326, 1251, 1124 cm-1. GC/MS (EI)
m/z found 393.5 ([M+H]+ 100%), Accurate Mass (ES+) m/z found [M+H]+ 393.1785,
C21H24F3N2O2 requires M 393.1789.
13 2-(4’-Nitrophenyl)-6-(pyrrolidin-1”-yl)-4-(pyrrolidine-1’’’-carbonyl)pyridine
Following procedure D and purification using EtOAc in hexane (0-50%) yielded the
o
title compound as a yellow solid (275 mg, 75%). mp 239.5-240.5 C. δH (500 MHz,
CDCl3) 8.29-8.21 (2H, m, 3’,5’-H), 8.21-8.14 (2H, m, 2’,6’-H), 7.1 (1H, s, 3-H), 6.4
(1H, s, 5-H), 3.7 (2H, t, J = 7.0 Hz, 2”’-H2), 3.60-3.49 (4H, m, 2”,5”-H2), 3.43 (2H, t, J
= 6.7 Hz, 5”’-H2), 2.06-2.01 (4H, m, 3”,4”-H2), 2.0 (2H, p, J = 7.0 Hz, 3”’-H2), 1.9 (2H,
p, J = 6.7 Hz, 4”’-H2); δC (125 MHz, CDCl3) 168.4 (C=O), 157.2 (C-6), 153.3 (C-2),
148.0 (C-4’), 146.9 (C-4), 145.8 (C-1’), 127.5 (C-2’,6’), 123.8 (C-3’,5’), 106.0 (C-3),
104.1 (C-5), 49.4 (C-5“’), 46.9 (C-2”,5”), 46.2 (C-2”’), 26.4 (C-4”’), 25.6 (C-3”,4”),
24.5 (C-3”’); νmax 1618, 1616, 1598, 1541, 1512, 1478, 1456, 1442, 1419, 1344, 1322,
1102, 858, 755, 702, 513 cm-1; m/z (LC-MS, ES+) 1121 ([M3Na]+, 38%), 755 ([M2Na]+,
81%), 366 ([M]+, 100%); Accurate mass (ES+) m/z found [MH]+ 367.1781; C20H23N4O3
requires M, 367.1770.
(17w) Methyl 6-chloro-5-(3-methoxyphenyl)pyridine-3-carboxylate
Following general procedure and purification using EtOAc in heptane (0-15%) yielded the
title compound as a white amorphous solid (229 mg, 76%). δH (700 MHz, CDCl3) 8.49 (1H,
d, J = 2.2, 6-H), 8.34 (1H, d, J = 2.2, 4-H), 7.48 (2H, m, 2’, 6’-H), 7.00 (2H, m, 3’, 5’-H),
4.10 (3H, s, 2-COCH3), 3.93 (3H, s, CO2CH3), 3.86 (3H, s, 4’-OCH3); δC (176 MHz, CDCl3)
165.7 (CO2CH3), 161.4 (C-2), 159.7 (C-4’), 148.2 (C-6), 139.7 (C-4), 129.8 (C-5), 129.3 (C-
1’), 128.0 (C-2’, 6’), 114.7 (C-3’, 5’), 113.9 (C-3), 55.5 (4’-OCH3), 54.6 (2-COCH3), 52.5
(CO2CH3); νmax (ATR) 1732, 1606, 1563, 1519, 1474, 1417, 1327, 1285, 1245, 1181, 1087,
1060, 1014 cm−1; Accurate Mass (ASAP) m/z found [M+H]+ 274.1075; C15H16NO4 requires
M, 274.1079.
(17’y) Methyl 6-fluoro-5-(4’-methoxyphenyl)pyridine-3-carboxylate
22

Following general procedure A and purification using EtOAc in hexane (0-50%) yielded the
title product as a pale yellow amorphous solid (107 mg, 58%). δH (600 MHz, CDCl3) 8.77
(1H, m, 6-H), 8.45 (1H, m, 4-H), 7.54 (2H, d, J = 8.6, 2’, 5’-H), 7.01 (2H, d, J = 8.6, 3’, 5’-
H), 3.96 (3H, s, CO2CH3), 3.86 (3H, s, OCH3); δC (151 MHz, CDCl3) 165.0 (CO2CH3), 162.6
(d, J = 246.2, C-6), 160.3 (C-4’), 147.8 (dd, J = 16.7, 5.1, C-6), 141.5 (d, J = 6.4, C-4), 130.2
(d, J = 6.4, C-2’, 6’), 125.1 (m, C-1’), 123.7 (d, J = 28.6, C-3), 114.5 (C-3’, 5’), 55.5 (OCH3),
52.7 (CO2CH3); δF (376 MHz, CDCl3) −65.4 (s); νmax (ATR) 1725, 1609, 1518, 1434, 1411,
1313, 1250, 1200, 1181, 1120, 1047, 1029 cm−1; Accurate Mass (ASAP) m/z found [M]+
261.0819; C14H12FNO3 requires M, 261.0801.
(20yB) Methyl 5-(4’-methoxyphenyl)-6-(morpholin-4”-yl)pyridine-3-carboxylate
Following general procedure B and purification using EtOAc in hexane (0-20%) yielded the
o
title compound as a light yellow solid (22 mg, 88%). mp 242-243 C. δH (599 MHz, CDCl3)
8.78 (1H, d, J = 2.3 Hz, 6-H), 7.97 (1H, d, J = 2.3 Hz, 4-H), 7.44 (2H, d, J = 8.3 Hz, 3’, 5’-
H), 6.95 (2H, d, J = 8.3 Hz, 3’, 6’-H), 3.88 (3H, s, CO2CH3), 3.84 (3H. s, 4’-OCH3), 3.62
(4H, t, J = 4.5 Hz, 3’’, 5’’-H2), 3.24 (4H, t, J = 4.5 Hz, 2’’, 6’’-H2). δC (151 MHz, CDCl3)
159.2 (C=O), 147.9 (C-4’), 140.7 (C-2), 131.4 (C-3), 128.7 (C-4), 127.8 (C-2’, 6’), 125.8 (C-
1’) , 124.8 (C-6), 118.5 (C-4), 114.4 (C-3’, 5’), 66.6 (-OCH3), 55.3 (CO2CH3), 51.9 (C-2’’,
6’’), 48.7 (C-3’’, 5’’). νmax (ATR) 2967, 2854, 1717, 1596, 1509, 1411, 1361, 1249, 1234,
1100 cm−1. m/z (LC-MS, ES+) 329.1 ([M+H]+, 100%), Accurate mass (ES+) m/z found
[M+H]+ 329.1511; C18H21N2O4 requires M, 329.1501.
(17y) Methyl 6-chloro-5-(4’-methoxyphenyl)pyridine-3-carboxylate
Following general procedure A and purification using CHCl3 in hexane (0-50%) yielded the
title compound as an off white solid (169 mg, 61%). mp 171-172 oC. δH (700 MHz, CDCl3)
8.93 (1H, d, J = 2.3 Hz, 6-H), 8.24 (1H, d, J = 2.3 Hz, 4-H), 7.42 (2H, d, J = 8.7 Hz, 2’, 6’-
H), 6.99 (2H, d, J = 8.7 Hz, 3’, 5’-H), 3.95 (3H, s, CO2CH3), 3.86 (3H, s, -OCH3). δC (176
MHz, CDCl3) 165.0 (C=O), 159.9 (C-4’), 153.8 (C-2), 148.9 (C-6), 140.2 (C-4), 136.5 (C-3),
130.5 (C-2’, 6’), 128.7 (C-1’), 125.2 (C-5), 113.9 (C-3’, 5’), 55.3 (4’-OCH3), 52.6 (CO2CH3).
νmax (ATR) 2960, 2849, 1726, 1614, 1591, 1523, 1446, 1394, 1317, 1252, 1181 cm−1. m/z
(LC-MS, ES+) 279.0 ([M(35Cl)+H]+, 100%), 281.1 ([M(37Cl)+H]+, 28%), Accurate mass
35
(ES+) m/z found [M(35Cl)+H]+ 278.0601, C14H13NO3 Cl requires M 278.0584.
23

(20yA) Methyl 5-(4’-methoxyphenyl)-6-(pyrrolidin-1”-yl)pyridine-3-carboxylate
Following general procedure B and purification using EtOAC in hexane (0-15%) yielded the
title compound as a light yellow amorphous solid (24 mg, 71%). δH (599 MHz, CDCl3) 8.03
(2H, J = 8.8 Hz, 3’, 5’-H), 7.46 (1H, d, J = 1.2 Hz, 6-H), 6.97 (2H, d, J = 8.8 Hz, 2’, 6’-H),
6.86 (1H, , d, J = 1.2 Hz, 4-H), 3.95 (3H, s, CO2CH3), 3.85 (2H, s, 4’-OCH3), 3.62 (2H, m,
2’’, 5’’-H2), 2.08 – 2.01 (1H, m, 3’’, 4’’-H2). δC (151 MHz, CDCl3) 166.7 (C=O), 160.5 (C-
4’), 157.0 (C-2), 155.6 (C-3), 139.1 (C-4), 128.3 (C-2’, 6’), 113.8 (C-3’, 5’), 113.1 (C-1’),
105.9 (C-6), 104.4 (C-4), 55.3 (-OCH3), 52.4 (CO2CH3), 47.0 (C-2’’, 5’’), 25.5 (C-3’’, 4’’).
νmax (ATR) 2972, 1731, 1607, 1557, 1518, 1477, 1459, 1246, 1216, 1178, 1030 cm−1. m/z
(LC-MS, ES+) 313.1 ([M+H]+, 100%), Accurate mass (ES+) m/z found [M+H]+ 313.1571,
C18H21N2O3 requires M 313.1552.
(17x) Methyl 6-chloro-5-[4’-(trifluoromethyl)phenyl]pyridine-3-carboxylate
Following General procedure A and purification using C18 reverse phase chromatography
(H2O: MeCN, 0-100%) yielded the title compound as an off white amorphous solid (173 mg,
55%). δH (599 MHz, CDCl3) 9.02 (1H, d, J = 2.3 Hz, 6-H), 8.27 (1H, d, J = 2.3 Hz, 4-H),
7.85 – 7.67 (2H, m, 3’, 5’-H ), 7.65 – 7.53 (2H, m, 2’, 6’-H), 3.98 (3H, s, CO2CH3). δC (151
MHz, CDCl3) 164.6 (C=O), 153.5 (C-2), 150.0 (C-6), 140.2 (C-4), 140.0 (C-1’), 135.5 (C-2),
131.01 (q, J = 32.8 Hz, C-4’) 129.7 (C-2’, 6’), 127.7 (C-4), 125.5 (q J = 3.7 Hz C-3’,5’),
123.8 (q, J = 269.4 Hz, -CF3) 52.7 (CO2CH3). δF (376 MHz, CDCl3) -62.73 (-CF3). νmax
(ATR) 3070, 2964, 1714, 1596, 1397, 1323, 1261, 1169, 1124, 1071 cm−1. m/z (LC-MS,
ES+) 316.4 ([M(35Cl)+H]+, 72%), 318.3 ([M(37Cl)+H]+, 22%), Accurate mass (ES+) m/z
found [M(35Cl)+H]+ 316.0359, C14H1035ClF3NO2 requires M 316.0352.
(20xA) Methyl 6-(pyrrolidin-1”-yl)-5-[4’-(trifluoromethyl)phenyl]pyridine-3-carboxylate
Following general procedure C and purification using EtOAc in hexane (0-15%) yielded the
title compound as a light yellow amorphous solid (36 mg, 88%). δH (599 MHz, CDCl3) 8.16
(2H, d, J = 8.1 Hz, 3’, 5’-H), 7.68 (2H, d, J = 8.1 Hz, 2’, 6’-H), 7.53 (1H, d, J = 1.2 Hz, 6-H),
6.95 (1H, d, J = 1.2 Hz, 4-H), 3.95 (3H, s, CO2CH3), 3.59 (4H, d, J = 6.4 Hz, C-2’’, 5’’-H2),
2.09 – 1.97 (4H, m, C-3’’, 4’’-H2). δC (151 MHz, CDCl3) 166.44 (C=O), 157.3 (C-2), 154.50
(C-5), 142.6 (C-3), 139.2 (C-1’), 130.7 (q, J = 32.6 Hz C-6’), 127.1 (C-3’, 5’), 125.35 (C-2’,
6’), 124.1 (q, J = 263.78 Hz, CF3), 106.9 (C-6), 106.1 (C-4), 52.5 (-OCH3), 47.0 (C-2’’, 5’’),
25.5 (C-3’’, 4’’). δF (376 MHz, CDCl3) δ -62.52. νmax (ATR) 2966, 2863, 1723, 1609, 1560,
24

1477, 1446, 1323, 1238, 1112 cm−1. m/z (LC-MS, ES+) 351.1 ([M+H]+, 100%), Accurate
mass (ES+) m/z found [M+H]+ 351.1308, C18H18F3N2O2 requires M 351.1320.
(18y) tert-Butyl 6-chloro-5-(4’-methoxyphenyl)pyridine-3-carboxylate
Following General procedure A and purification using EtOAc in hexane yielded the title
o
compound as an off white solid (140 mg 44%). mp. 177-178 C (methanol). δH (599 MHz,
CDCl3) 8.86 (1H, d, J = 2.5 Hz, 6-H), 8.16 (1H, d, J = 2.4 Hz, 4-H), 7.39 (2H, d, J = 9.1, 2’,
6’-H), 6.99 (2H, d, J = 9.1 Hz, 3’, 5’-H), 3.86 (3H, s, 4’-OCH3), 1.59 (9H, s, (CH3)3). δC (151
MHz, CDCl3) 163.6 (C=O), 159.9 (C-4’), 153.3 (C-2), 148.9 (C-6), 140.1 (C-4), 136.3 (C-3),
130.5 (C-2’, 6’), 129.0 (C-1’), 126.9 (C-5), 113.9 (C-3’ 5’), 82.5 (-C(CH3)3), 55.3 (-OCH3),
28.1 (C(CH3)3). νmax (ATR) 2987, 2830, 2164, 1726, 1593, 1400, 1258, 1136, 1033 cm−1. m/z
(LC-MS, ES+) 320.1 ([M(35Cl)+H]+, 46%), 322.1 ([M(37Cl)+H]+, 18%), 264.0 ([M(35Cl)-
tBu+H]+, 100%), 266.0 ([M(37Cl)-tBu+H]+, 38%)
Accurate mass (ES+) m/z found
[M(35Cl)+H]+ 320.1075, C17H1935ClNO3 requires M 320.1053.
(21yA) tert-Butyl 5-(4’-methoxyphenyl)-6-(pyrrolidin-1”-yl)pyridine-3-carboxylate
Following general procedure D and purification using EtOAC in hexane (0-20%) yielded the
title compound as a light yellow solid (26 mg, 75%). mp 248-249 oC (ethanol). δH (700 MHz,
CDCl3) 8.73 (1H, d, J = 2.2 Hz, 6-H), 7.83 (d, J = 2.2 Hz, 1H), 7.24 – 7.20 (2H, m, 2’, 6’-H),
6.91 – 6.87 (2H, m, 3’, 5’-H), 3.83 (3H, s, 4’-OCH3), 3.17 – 3.23 (4H, m, 2’’, 5’’-H2), 1.79 –
1.75 (4H, m, 3’’, 4’’-H2), 1.54 (9H, s, C(CH3)3). δC (176 MHz, CDCl3) 165.3 (C=O), 158.6
(C-4’), 148.2 (C-6), 140.6 (C-4), 132.4 (C-1’) 130.1 (C-2’, 6’), 128.3 (C-2), 127.8 (C-3),
116.7 (C-5) 113.4 (C-3’, 5’), 80.5 (C(CH3)3), 55.7 (-OCH3), 50.3 (C-2’’, 5’’), 28.3 (C(CH3)3),
25.6 (C-3’’, 4’’). νmax (ATR) 2985, 2880, 2256, 1699, 1598, 1513, 1459, 1308, 1251, 1166
cm−1. m/z (LC-MS, ES+) 355.2 ([M+H]+, 100%), Accurate mass (ES+) m/z found [M+H]+
355.2033, C21H27N2O3 requires M 355.2022
(21yB) tert-Butyl 5-(4’-methoxyphenyl)-6-(morpholin-4”-yl)pyridine-3-carboxylate
Following general procedure D and purification using EtOAC in hexane (0-20%) yielded the
title compound as a light yellow amorphous solid (30 mg, 87%). δH (700 MHz, CDCl3) 8.74
(1H, d, J = 2.3 Hz, 6-H), 7.92 (1H, d, J = 2.3 Hz, 4-H), 7.45 (2H, d, J = 8.7 Hz, 2’, 6’-C),
6.95 (2H, d, J = 8.7 Hz, 3’, 5--H), 3.84 (3H, s, 4’-OCH3), 3.61 (4H, t, J = 4.7 Hz, 3’’, 5’’-H2),
3.21 (4H, t, J = 4.7 Hz, 2’’, 6’’-H2), 1.56 (9H, s, C(CH3)3). δC (176 MHz, CDCl3) 164.9
25

(C=O), 159.1 (C-4’), 147.7 (C-5), 140.5 (C-4), 131.6 (C-1’), 128.8 (C-2’’, 6’’), 125.7 (C-2),
124.7 (C-3), 120.4 (C-5), 114.3 (C-3’’, 5’’), 81.1 (C(CH3)3), 66.6 (C-2’’, 6’’), 55.3 (-OCH3),
48.8 (C-3’’, 5’’), 28.3 (C(CH3)3). νmax (ATR) 2967, 2246, 1731, 1569, 1414, 1320, 1112
cm−1. m/z (LC-MS, ES+) 371.2 ([M+H]+, 100%), Accurate mass (ES+) m/z found [M+H]+
371.2000, C21H26N2O4 requires M 371.1971.
(18x) tert-Butyl 6-chloro-5-[4’-(trifluoromethyl)phenyl]pyridine-3-carboxylate
Following General procedure A and purification using C18 reverse phase chromatography
(H2O: MeCN, 0-100%) yielded the title compound as a white solid (177 mg, 32%). mp 105-
o
106 C. δH (700 MHz, CDCl3) 8.95 (1H, d, J = 2.3 Hz, 6-H), 8.18 (1H, d, J = 2.3 Hz, 3-H),
7.78 – 7.71 (2H, m, 2’,6’-H), 7.61 – 7.56 (2H, m, 3’-5’-H), 1.61 (9H, s, C(CH3)3). δC (176
MHz, CDCl3) 163.2 (C=O), 152.9 (C-2), 150.0 (C-6), 140.24 (C-1’), 140.1 (C-4), 135.2 (C-
3), 130.8 (q, J = 32.7 Hz, C-4‘) 129.7 (C-2’’, 6’’), 127.1 (C-5), 125.4 (q, J = 3.7 Hz, C-3’’,
5’’) 123.8 (q, J = 272.6 Hz, -CF3) 82.9 (C(CH3)3), 28.1 (C(CH3)3). δF (376 MHz, CDCl3) -
62.70 (-CF3). νmax (ATR) 2983, 2930, 1723, 1623,1598, 1392, 1320, 1261, 1112 cm−1. m/z
(LC-MS, ES+) 358.1 ([M(35Cl)+H]+, 42%), 360.1 ([M(37Cl)+H]+, 15%), 302.0 ([M(35Cl)-
tBu+H]+, 100%), 304.0 ([M(37Cl)-tBu+H]+, 38%)
Accurate mass (ES+) m/z found
[M(35Cl)+H]+ 358.0828, C17H1635ClNO2F3 requires M 358.0822.
(21xB) tert-Butyl 6-(morpholin-4”-yl)-5-[4’-(trifluoromethyl)phenyl]pyridine-3-carboxylate
Following general procedure D and purification using EtOAC in hexane (0-20%) yielded the
title compound as an off white amorphous solid (41 mg, 82%) δH (599 MHz, CDCl3) 8.80
(1H, d, J = 2.2 Hz, 6-H), 7.95 (1H, d, J = 2.2 Hz, 4-H), 7.67 (4H, m, Ar-H), 3.60 (4H, t, J =
4.7 Hz, 3’’, 5’’-H2), 3.20 (4H, t, J = 4.7 Hz, 2’’, 6’’-H2), 1.56 (9H, s, C(CH3)3). δC (151 MHz,
CDCl3) 164.6 (C=O), 160.8 (C-2), 149.1 (C-6), 143.26 (C-1’), 140.8 (C-4), 129.9 (q, J = 33.1
Hz C-4’)), 127.9 (C-2’, 6’), 125.9 (q, J = 3.7 Hz, C-3’, 5’), 123.9 (q, J = 278.0 Hz, -CF3)
120.47 (C-5), 81.3 (-C(CH3)3, 66.4 (C-3’’, 5’’), 49.1 (C-2’’, 6’’), 28.2 (C(CH3)3). δF (376
MHz, CDCl3) -62.55 (-CF3). νmax (ATR) 2950, 2829, 1729, 1678, 1610, 1497, 1343, 1265,
1184 cm−1. m/z (LC-MS, ES+) 409.1 ([M+H]+, 100%), 353.1 ([M-tBu+H]+, 52%), Accurate
mass (ES+) m/z found [M+H]+ 409.1750, C21H24F3N2O3 requires M 409.1739.
(22zA) Methyl 5-(4’-nitrophenyl)-2-(pyrrolidin-1”-yl)pyridine-3-carboxylate
26

Following general procedure A gave the crude aryl-nicotinate intermediate which was used
without further purification according to general procedure C to yield, upon purification
using EtOAc in hexane (0-25%) the title compound as a dark yellow amorphous solid (62
mg, 32%), δH (700 MHz, CDCl3) 8.58 (1H, d, J = 2.5 Hz, 6-H), 8.27 (2H, d, J = 8.8 Hz, 3’,
5’-H), 8.17 (1H, d, J = 2.5 Hz, 3-H), 7.67 (2H, d, J = 8.8 Hz, 2’, 6’-H), 3.93 (3H, s,
CO2CH3), 3.51 (4H, d, J = 6.6 Hz, 2’’, 5’’-H2), 1.99 (4H, d, J = 6.6 Hz, 3’’, 4’’-H2). δC (176
MHz, CDCl3) 167.2 (C=O), 155.42 (C-2), 152.92 (C-3), 146.6 (C-4’), 130.41 (C-6), 129.00,
126.2, (C-2’’, C-6’’), 124.4 (C-3’, 5’), 121.5 (C-5), 117.48 (C-1’), 52.49 (CO2CH3), 50.30
(C-2’’, 5’’), 25.58 (C-3’’, 4’’). νmax (ATR) 2925, 2291, 1970, 1757, 1669, 1561, 1533, 1371,
1280, 1168 cm−1. m/z (LC-MS, ES+) 328.1 ([M+H]+, 100%), Accurate mass (ES+) m/z found
[M+H]+ 328.1291, C17H18N3O4 requires M 328.1297.
(19y) Methyl 2-chloro-5-(4’-methoxyphenyl)pyridine-3-carboxylate
Following general procedure A and purification using EtOAc in hexane (0-25%) yielded the
title compound as a white amorphous solid. Purification using (0-35% EtOAc-hexane,)
afforded the title compounds as an amorphous white solid (55 mg, 20%) δH (700 MHz,
CDCl3) 8.71-8.64 (1H, m, 6-H), 8.30 (1H, d, J = 2.5, 4-H), 7.54-7.50 (2H, m, 2-H), 7.04-6.98
(2H, m, 3',5’-H), 3.98 (3H, s, CO2CH3), 3.86 (3H, s, 4'-OCH3); δC (176 MHz, CDCl3) 165.1
(C=O), 160.3 (C-2), 149.5 (C-6), 147.8 (C-5), 137.9 (C-4), 135.2 (C-1), 128.2 (C-2'), 127.7
(C-1’), 126.4 (C-3), 114.8 (C-3'), 55.4 (5'-OCH3), 52.9 (CO2CH3); νmax (ATR) 3019, 2961,
2933, 2839, 1737 (s) (C=O), 1608, 1582, 1552, 1515, 1324, 1310, 1293, 1226, 1184, 1064,
1054, 1033, cm−1. m/z (LC-MS, ES+) [M+H]+ 279.8 (100), Accurate mass (ES+) m/z found
[M+H]+ 278.0583, C14H13NO3Cl requires M 278.0584.
(22yB) Methyl 5-(4”-methoxyphenyl)-2-(morpholin-4’-yl)pyridine-3-carboxylate
Following general method C and purification using EtOAc in heptane (20-30%) yielded the
title product as a white amorphous solid (141 mg, 93%). δH (700 MHz, CDCl3) 8.51 (1H, s,
6-H), 8.20 (1H, s, 4-H), 7.47 (2H, d, J = 8.0, 2’’,6’’-H), 6.98 (2H, d, J = 8.0, 3’’, 5’’-H), 3.91
(3H, s, CO2CH3), 3.85 (7H, m, OCH3, 3’, 5’-H2), 3.44 (4H, m, 2’, 6’-H2); δC (176 MHz,
CDCl3) 167.5 (CO2CH3), 159.3 (C-4’’), 158.2 (C-2), 148.4 (C-6), 138.8 (C-4), 129.5 (C-1’’),
127.6 (C-5), 127.4 (C-2’’, 6’’), 114.5 (C-3’’, 5’’), 113.6 (C-3), 66.9 (C-3’, 5’), 55.4 (OCH3),
52.2 (CO2CH3), 49.9 (C-2’’, 6’’); νmax (ATR) 1717, 1601, 1472, 1440, 1246, 1212, 1182,
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1114, 1087 cm−1; Accurate Mass (ESI) m/z found [M+H]+ 329.1510; C18H21N2O4 requires M,
329.1501.
(22yC) Methyl 5-(4”-methoxyphenyl)-2-(piperidin-1’-yl)pyridine-3-carboxylate
Following general procedure C and purification using EtOAc in heptane yielded the title
compound as a yellow amorphous solid (57 mg, 89%). δH (700 MHz, CDCl3) 8.47 (1H, d, J =
2.4, 6-H), 8.11 (1H, d, J = 2.4, 4-H), 7.45 (2H, d, J = 8.6, 2’’, 6’’-H), 6.97 (2H, d, J = 8.6, 3’’,
5’’-H), 3.91 (3H, s, CO2CH3), 3.84 (3H, s, OCH3), 3.39 (4H, m, 2’, 6’-H2), 1.68 (6H, m, 3’,
4’, 5’-H2); δC (176 MHz, CDCl3) 168.4 (CO2CH3), 159.2 (C-4’’), 158.6 (C-2), 148.3 (C-6),
138.7 (C-4), 130.0 (C-1’’), 127.5 (C-2’’, 6’’), 126.4 (C-5) 114.6 (C-3’’, 5’’), 113.4 (C-3),
55.5 (OCH3), 52.3 (CO2CH3), 50.7 (C-2’, 6’), 26.1 (AlkC), 24.7 (AlkC); υmax (ATR) 1716,
1694, 1608, 1441, 1247, 1180 cm−1; Accurate Mass (ESI) m/z found [M+H]+ 327.1701;
C19H23N2O3 requires M, 327.1709.
(22yE) Methyl 2-(butylamino)-5-(4’-methoxyphenyl)pyridine-3-carboxylate
Following general procedure C and purification using EtOAC in hexane (0-20%)
yielded the title compound as a yellow amorphous solid (38 mg, 60%). δH (700 MHz,
CDCl3) 8.50 (1H, d, J = 2.5 Hz, 6-H), 8.32 (1H, d, J = 2.5 Hz, 4-H), 7.42 (2H, d, J = 8.7
Hz, 2’, 6’-H), 6.96 (2H, d, J = 8.7 Hz, 3’, 5’-H), 3.89 (3H, s, CO2CH3), 3.83 (3H, s, 4’-
OCH3), 3.60-3.52 (2H, m, 1’’-H2), 1.71 – 1.63 (2H, m, 2’’-H2), 1.52 – 1.42 (2H, m, 3’’-
H2), 0.97 (3H, t, J = 7.4 Hz, 4’’-H3). δC NMR (176 MHz, CDCl3) 162.6 (C=O), 159.0
(C-4’), 152.9 (C-2), 146.4 (C-6), 138.6 (C-4), 131.0 (C-1’), 127.1 (C-2’, 6’), 123.9 (C-
5), 117.8 (C-4), 114.4 (C-3’, 5’), 67.1 (C-1’’), 55.4 (-OCH3), 52.0 (CO2CH3), 31.6 (C-
2’’), 20.3 (C-3’’), 13.9 (C-4’’). υmax (ATR) 3381, 2960, 2259, 1693, 1611, 1504, 1243,
1036 cm−1. m/z (LC-MS, ES+) 313.3 ([M-H]-, 100%), Accurate mass (ES+) m/z found
[M+H]+ 315.1705, C18H23N2O3 requires M 315.1709.
(19’y) Methyl 2-fluoro-5-(4-methoxyphenyl)pyridine-3-carboxylate
Following general procedure A, and purification using EtOAc in heptane (0-20% ) yielded
the title product as an off-white amorphous solid (715 mg, 62%). δH (700 MHz, CDCl3) 8.51
(2H, m, 4, 6-H), 7.50 (2H, m, 2’, 6’-H), 7.01 (2H, m, 3’, 5’-H), 3.98 (3H, s, CO2CH3), 3.86
(OCH3); δC (176 MHz, CDCl3) 164.0 (d, J = 8.1, CO2CH3), 160.5 (d, J = 249.8, C-2), 160.3
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(C-4’), 149.1 (d, J = 15.4, ArC), 141.7 (d, J = 1.6, ArC), 135.0 (C-5), 128.3 (C-2’, 6’), 128.0
(C-1’), 114.9 (C-3, 5’), 113.4 (d, J = 25.6, C-3), 55.6 (OCH3), 53.0 (CO2CH3); δF (376 MHz,
CDCl3) −66.3 (s); νmax (ATR) 1722, 1603, 1459, 1446, 1327, 1292, 1249, 1179, 1089, 1042,
977 cm−1; Accurate Mass (ASAP) m/z found [M]+ 261.0824; C14H12FNO3 requires M,
261.0801
(19’’y) Methyl 2-methoxy-5-(4-methoxyphenyl)pyridine-3-carboxylate
Following general procedure A and purification using EtOAc in heptane (0-15%)
yielded the title compound as a white amorphous solid (229 mg, 76%). δH (700 MHz,
CDCl3) 8.49 (1H, d, J = 2.2, 6-H), 8.34 (1H, d, J = 2.2, 4-H), 7.48 (2H, m, 2’, 6’-H),
7.00 (2H, m, 3’, 5’-H), 4.10 (3H, s, 2-OCH3), 3.93 (3H, s, CO2CH3), 3.86 (3H, s, 4’-
OCH3); δC (176 MHz, CDCl3) 165.7 (CO2CH3), 161.4 (C-2), 159.7 (C-4’), 148.2 (C-6),
139.7 (C-4), 129.8 (C-5), 129.3 (C-1’), 128.0 (C-2’, 6’), 114.7 (C-3’, 5’), 113.9 (C-3),
55.5 (4’-COCH3), 54.6 (2-COCH3), 52.5 (CO2CH3); νmax (ATR) 1732, 1606, 1563,
1519, 1474, 1417, 1327, 1285, 1245, 1181, 1087, 1060, 1014 cm−1. Accurate Mass
(ASAP) m/z found [M+H]+ 274.1075; C15H16NO4 requires M, 274.1079.
(19x) Methyl 2-chloro-5-[4’-(trifluoromethyl)phenyl]pyridine-3-carboxylate
Following general procedure A and purification using EtOAc in hexane (0-15%) to yield the
title compound as a white amorphous solid (64 mg, 24%); δH (700 MHz, CDCl3) 8.74 (1H,
m, 6-H), 8.,37 (1H, d, J = 2.1, 4-H), 7.77 (2H, d, J = 8.1, C-2’, 6’), 7.70 (2H, d, J = 8.1, C-3’,
5’), 4.00 (3H, s, CO2CH3). δC (176 MHz, CDCl3) δ 164.9 (C=O), 149.9 (C-2), 149.8 (C-6),
139.1 (C-5), 138.9 (C-4), 134.2 (C-1’), 131.2 (q, J=33.2 Hz, C-4’), 127.7 (C-2’, 6’), 126.5 (q,
J=3.8 Hz, C-3’, 5’)), 124.0 (q, J=272.0 Hz, -CF3), 121.5 (C-3), 53.2 (CO2CH3), δF (376 MHz,
CDCl3) δ -62.83 (-CF3); νmax (ATR) 2174, 1982, 1730 (C=O), 1555, 1520, 1414, 1224, 1111,
1052, 1033, 962, cm-1; m/z (LCMS-ESI) 318 ([M(37Cl)]+, 31%), 316 ([M(35Cl)+H]+), 100),
35
Accurate Mass (ESI-TOF) m/z Found [M+H]+ 316.0345, C14H20NO2F3 CI requires M
316.0352.
(22xA) Methyl 2-(pyrrolidin-1”-yl)-5-[4’-trifluoromethylphenyl]pyridine-3-carboxylate
Following general procedure C and purification using EtOAc in hexane (0-20%) yielded the
title compound as an amorphous white solid (23 mg, 50%). δH (700 MHz, CDCl3) 8.53 (1H,
bs, 6-H), 8.11 (1H, d, J = 2.2, 4-H), 7.69-7.61 (4H, m, Ar), 3.92 (3H, s, CO2CH3), 3.47-3.45
(4H, m, 2", 5"-H2), 1.97-1.94 (4H, m, 3",4"-H2); δC (176 MHz, CDCl3) 167.7 (C=O), 155.3,
29