Diversification of 6-bromo-2-substituted Pyridine Derivatives via Suzuki-Miyaura Cross-Coupling

Article abstract of DOI:10.1002/jhet.3144

The functionalized pyridine ring is a ubiquitous moiety in numerous research areas including materials, natural products, as well as agrochemicals and is a strategic synthon for heteroaromatic synthetic method development. Pyridinyl ligand scaffolds are also frequently incorporated into the study of metal complexes for pharmaceutical applications or separation science. Convergent access to advanced synthons is critical to experimentally defining structure activity relationships and improvement of molecular performance in the aforementioned areas. The current work describes an efficient catalyst/ligand combination for accessing 2-acetyl- and 2-procarbonyl substituted pyridines via Suzuki-Miyaura cross-coupling with various organotrifluoroborates. Twenty examples are described with carbonyl and procarbonyl functional groups which afford subsequent access to diversified unsymmetric ketones. Substrate scope and limitation in addition to?a scale up experiment are reported.

Full text of DOI:10.1002/jhet.3144

Month 2018 Diversification of 6-bromo-2-substituted Pyridine Derivatives via Suzuki-
Miyaura Cross-Coupling
Abigail E. Lambert and Jesse D. Carrick*
Department of Chemistry, Tennessee Technological University, 55 University Drive, Cookeville, TN 38505-0001, USA
*
E-mail: jcarrick@tntech.edu
Received November 16, 2017
DOI 10.1002/jhet.3144
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
The authors dedicate this work in memory of TTU Professor Emeritus Scott H. Northrup (1951-2018)
Pd(OAc) (5 mol%),
2
RuPhos (10 mol%)
3
R BF K (1.1 equiv),
3
Cs CO (3 equiv)
2
3
R1
R1
N
R2
30-93%)
0 Examples
N
Br
o
Tol:H O (4:1), 110 C, 16 h
2
(
2
PCy2
1
2
R = C(O)CH , CHO, CN,
R = alkyl, aryl, styrenyl,
3
O
O
or C(O)N(OCH )CH3
or heteroaryl
3
RuPhos
The functionalized pyridine ring is a ubiquitous moiety in numerous research areas including materials,
natural products, as well as agrochemicals and is a strategic synthon for heteroaromatic synthetic method
development. Pyridinyl ligand scaffolds are also frequently incorporated into the study of metal complexes
for pharmaceutical applications or separation science. Convergent access to advanced synthons is critical to
experimentally defining structure activity relationships and improvement of molecular performance in the
aforementioned areas. The current work describes an efficient catalyst/ligand combination for accessing
2
-acetyl- and 2-procarbonyl substituted pyridines via Suzuki-Miyaura cross-coupling with various
organotrifluoroborates. Twenty examples are described with carbonyl and procarbonyl functional groups
which afford subsequent access to diversified unsymmetric ketones. Substrate scope and limitation in
addition to a scale up experiment are reported.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
various aryl and heteroaryl halide electrophiles. In
the current work, the polarities of the participating reagents
Functionalized pyridines are an important class of
synthons for the development of active pharmaceutical
ingredients [1], natural products [2], complexant
scaffolds for separations [3], as well as pyridinyl
thiosemicarbazones (PTSCs) and related metal complexes.
PTSCs have demonstrated efficacy against several areas
of unmet clinical need including potential antibacterial and
anticancer chemotherapeutics [4] via suspected generation
of redox-active Fe complexes in vivo [5]. Selective,
convergent methods for the reliable construction of
advanced ligand scaffolds and metal–ligand candidates
for structure–activity relationships and subsequent lead
optimization is predicated on rapid access to diversified
structures. Metal-mediated coupling of halo pyridines,
especially with the oxidative addition site adjacent to the
are
orthogonal
to
the
aforementioned
as
organotrifluoroborates [9] were used as the transmetallating
reagent with the substrate 2-acetyl-6-bromopyridine and
other procarbonyl derivatives towards future construction
of PTSCs. Recently we described an efficient approach
to the synthesis of soft-Lewis basic heteroaromatic
complexant scaffolds with potential applications in
separation science by employing a Suzuki-Miyaura cross-
coupling [10] strategy with Pd(OAc) , the dialkylbiaryl
phosphine ligand RuPhos, [11] and various sp and sp
2
2
3
hybridized potassium organotrifluoroborates [12] with
numerous functionalized 6-bromo-2-pyridinyl-[1,2,4]-
triazinyl substrates. We were interested in validating the
scope of the described method for the current substrates
amenable to forming various PTSCs and related metal
complexes. PTSC-metal complexes can be accessed in a
straightforward manner via condensation with an
appropriate thiosemicarbazide followed by complexation
with an appropriate metal. With the aforementioned goals
in mind, we set out to assess the efficacy of this
heteroatom, is
a traditionally challenging synthetic
transformation. Contemporary approaches by Burke [6],
Yamamoto [7], and others [8] have advanced this important
area of research by incorporating the use of functionalized
pyridinyl reagents as nucleophiles for coupling with
©
2018 Wiley Periodicals, Inc.

A. E. Lambert and J. D. Carrick
Vol 000
transformation for the production of 2-carbonyl
derivatives of 6-bromopyridine. Method validation,
initial and expanded substrate scope with respect to
functional groups amenable to carbonyl formation with
various organotrifluoroborates, current substrate structural
limitations, and a scale-up experiment are described herein.
catechol trifluoroborate rounded out the successful
examples executed with product 13 afforded in a similar
yield (77%) to the other aromatic examples (entries 4–7).
With a thorough preliminary nucleophile screening for
the desired scaffold completed we set out to investigate
the feasibility of functional group interconversion with
other carbonyl derivative substrates and various potassium
organotrifluoroborates.
RESULTS AND DISCUSSION
Table 2 highlights coupling examples involving 2-
cyano, 2-formyl, and 2-carboxylic acid methoxy-methyl-
amide-6-bromopyridine. Entries (1 and 7) employing
6-bromopyridine-2-carbonitrile afforded the desired
coupling products with heteroaromatic and homologous
aromatic transmetallating reagents thereby demonstrating
aptitude for the reaction conditions utilized. Entry 2 with
the 2-formyl substituent describes a difficult substrate
with potential for oxidative degradation and/or dative
bidentate chelation to the putative catalyst/ligand
system leading to deleterious reaction outcomes. The
aforementioned were not observed in the case of product
15 which was afforded in 93% yield. The Weinreb [21]
(entries 3 and 6) and related morpholine amides present
numerous opportunities for diversification through the
simple addition of hard nucleophiles post Suzuki-Miyaura
cross-coupling and were defined in the context of
the present work. In order to facilitate acquisition of the
desired pyridinyl Weinreb amide coupling products
synthesis of the starting material was required. Thus,
treatment of 6-bromo-pyridine-2-carboxylic acid with
the requisite Weinreb imidazole carbamate (WImC) via
a one pot process by the Heller-Sarpong procedures [22]
afforded the desired amidation product in 67% average
yield over two steps. Treatment of 2-carboxylic acid
methoxy-methyl-amide-6-bromo pyridine with an
electron-rich direct connect aryl coupling reagent (entry
3) or a styrenyl derivative (entry 6) afforded the desired
coupling products 16 and 19 in 30% in the case of
the former and 70% in the case of the latter [23]. The
procarbonyl cyano group also proved to be a competent
substrate for the investigated conditions leading to the
production of the phenyl (entry 4) [24] and 4-tert-
butylphenyl derivative (entry 5). Three additional
substrates including: 6-bromo-pyridine-2-carboxylic acid,
6-bromo-pyridine-2-carbaldehyde oxime [25], and 1-(6-
bromo-pyridin-2-yl)-ethanone oxime proved obstinate
with the current conditions resulting in incomplete
conversion of starting material and/or the provision of
complex product mixtures. To validate the applicability
of the described transformation for processes which
supersede development scale, a scale-up reaction was
performed using a previously successful experiment
(Table 1) as an initial guide (Scheme 1).
The Suzuki-Miyaura cross-coupling reaction presents
strategic advantages for diversification of carbonyl
substituted heteroaromatic scaffolds without the inherent
risk for simple addition to the carbonyl moiety as an
unwanted side reaction during the transformation. Diverse
options for catalyst/ligand combinations, transmetallating
reagents, mild reaction conditions, in addition to
numerous commercially available materials render this
transformation significant for substrate functionalization.
Conversely, the use of organomagnesium reagents in the
context of the Kumada coupling with pyridinyl ketones
can present potential difficulties including unwanted
addition to the pyridine ring or resident carbonyl
functionality [13]. The preliminary substrate scope
definition with organotrifluoroborates in the context of
the initial substrate 6-bromo-2-acetylpyridine is
delineated below in Table 1. A variety of alkyl, aryl, and
heteroaryl organotrifluoroborates were attempted. Simple
alkyl coupling reagents such as potassium butyl (entry 1)
and potassium 3,3-dimethylbutyltrifluoroborate (entry 2)
proved competent for the described transformation
affording the desired products 1 and 2 in 81 and 77%
isolated, purified yield, respectively. Derivatization using
the phenethyl reagent was also successful (entry 3) [14].
Exploration of phenyl (entry 4) [15] and substituted
aryl coupling reagents (entries 5–7) were also possible
with inductive (entry 5) [16] and resonance donating
effects (entries 6–7) [17] of substituents providing
little difference in observed yields. Potassium vinyl
trifluoroborates with a phenyl (entry 8) and saturated
cyclohexyl (entry 9) ring were possible, although
obtained in a lower overall yield for products 8 and 9
[
18] relative to the direct aryl coupling examples
2
described previously. The pseudo sp hybridization of the
cyclopropyl coupling reagent frequently presents
challenges [19] for Suzuki-Miyaura cross-coupling and
entry 10 was no exception [20]. Heteroaryl coupling
reagents leading to the production of 11 and 12 afforded
the desired products. Entry 11 presents a challenging
metal-mediated coupling with the requisite oxidative
addition taking place at the 2-position relative to the
heteroatom on the pyridinyl scaffold in addition to the
transmetallating coupling partner also residing at the 2-
position of the thiophene. Entry 13 with potassium
Treatment of 6-bromo-2-acetylpyridine with potassium
phenyltrifluoroborate on 2.5 mmol scale, which
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthetic Access to Functionalized 2-carbonyl and Procarbonyl
Pyridine Synthons
Table 1
Suzuki-Miyaura cross-coupling of 6-bromo-2-acetylpyridine with various organ otrifluoroborates.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. E. Lambert and J. D. Carrick
Vol 000
Table 2
Suzuki-Miyaura cross-coupling of 6-bromo-pyridinyl procarbonyl synthons with varous organotriflu oroborates.
Scheme 1. Suzuki-Miyaura coupling of 6-bromo-2-acetylpyridine scale-
CONCLUSIONS
up experiment.
Pd(OAc)2 (5 mol%),
RuPhos (10 mol%)
In summary, we have demonstrated a practical
transformation for the acquisition of various
functionalized 2-acetyl- and 2-procarbonylpyridinyl
derivatives through Suzuki-Miyaura cross-coupling
utilizing Pd(OAc)2 and RuPhos as an efficient
catalyst/ligand combination highlighted by 15 examples
PhBF3K (1.1 equiv)
Cs2CO3 (3 equiv)
,
N
Br
N
Ph
Tol:H2O (4:1), 110 oC, 16 h
.5 mmol Scale
O
O
4
(
88%)
2
(9 novel) not previously disseminated in the primary
literature in (30–93%) isolated yield. The transformation
provides a coherent strategy for rapid diversification of
represented a five-fold increase in substrate concentration,
afforded the desired product in increased yield to the
development-scale transformation.
electrophilic
scaffolds
with
alkyl,
aryl,
and
heteroaromatic coupling reagents towards synthon or
library development. Compounds 14; 16–20 afford
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthetic Access to Functionalized 2-carbonyl and Procarbonyl
Pyridine Synthons
1
3
opportunities to potentially access any unsymmetric ketone
derivative through use of an appropriate alkyl lithium or
Grignard reagent and provide further guidance on dative
Lewis basic functionality tolerance in metal-mediated
coupling experiments.
CH3 × 3); C NMR (125 MHz, CDCl ): δ 201.1
3
(C=O), 162.9 (Ar-C), 153.3 (Ar-C), 137.0 (Ar-CH),
126.1 (Ar-CH), 118.8 (Ar-CH), 44.0 (CH ), 33.8 (CH ),
30.7 (C), 29.5 (CH × 3), 25.9 (CH ); IR (ATR-CDCl ):
ῡmax = 3065, 2955, 2867, 1700, 1587, 1454, 1356, 812,
2
2
3
3
3
À1
6
02, 587 cm
;
HRMS (EI): m/z calculated for
C H NO: 205.1469; found: 205.1463.
13
19
EXPERIMENTAL
1
-[6-(4-Dimethylamino-phenyl)-pyridin-2-yl]-ethanone
(
7).
R = 0.53, 10% EtOAc:hexanes; EtOAc/hexanes
F
General.
All reagents were purchased from U.S.
(
gradient); pale-yellow solid; mp = 147.9–150.0°C;
1
chemical suppliers, stored according to published protocols,
and used as received unless indicated otherwise. All
experiments were performed in oven- or flame-dried
glassware under an inert atmosphere of Ar except where
indicated. Reaction progress was monitored using thin-
isolated yield 0.079 g, 63%; H NMR (500 MHz,
CDCl ): δ 8.03–7.99 (m, 2H, Ph-H), 7.84–7.74 (m, 3H,
Ar-H), 6.84–6.78 (br-m, 2H, Ph-H), 3.06 (s, 6H,
CH3 × 2), 2.83 (s, 3H, CH3); C NMR (125 MHz,
CDCl ): δ 201.2 (C=O), 156.8 (Ar-C), 153.3 (Ar-C),
1
C), 122.2 (Ar-CH), 118.4 (Ar-CH), 112.4 (Ph-CH), 40.6
3
13
3
layer chromatography on glass-backed silica gel plates
51.5 (Ph-C), 137.4 (Ar-CH), 127.9 (Ph-CH), 126.3 (Ph-
1
and/or H NMR analysis of crude reaction mixtures. R
F
values for compounds that resulted in a concentrically
observed spot on normal phase silica gel are reported using
the conditions listed. All reported yields listed are for pure
compounds and corrected for residual solvent, if applicable,
(
CH × 2), 26.0 (CH ); IR (ATR-CDCl ): ῡ
= 2924,
max
3
3
3
1
8
2
695, 1609, 1582, 1529, 1442, 1367, 1313, 1203,
À1
06 cm ; HRMS (EI): m/z calculated for C H N O:
15 16 2
40.1263; found: 240.1260.
1
from H NMR spectroscopy unless otherwise indicated.
1
-(6-Styryl-pyridin-2-yl)-ethanone (8). R = 0.61, 10%
F
Infrared spectral data was acquired from the (form) listed.
EtOAc:hexanes; EtOAc/hexanes (gradient), yellow solid;
mp = 54.7–56.8°C; isolated yield 0.085 g, 61%; H NMR
1
13
1
All H and C NMR chemical shifts are reported using the
δ scale and are referenced to the residual solvent signal:
(500 MHz, CDCl ): δ 7.89 (dd, J = 7.8, 1.0 Hz, 1H, Ar-
3
1
CDCl (δ 7.26) for H–NMR and chloroform (δ 77.16) for
3
H), 7.79 (t, J = 7.8 Hz, 1H, Ar-H), 7.74 (d, J = 16.0 Hz,
H, vinyl H). 7.63–7.60 (m, 2H, Ph-H), 7.54 (dd,
J = 7.8, 1.0 Hz, 1H, Ar-H), 7.45–7.38 (m, 2H, Ph-H),
.35–7.31 (m, 1H, Ph-H), 7.22 (d, J = 16.0 Hz, 1H, vinyl
13
C–NMR. Splittings are reported as follows: (s) = singlet,
1
(
(
d) = doublet, (t) = triplet, (dd) = doublet of doublets,
dt) = doublet of triplets, (br) = broad, and (m) = multiplet.
7
13
High resolution mass spectrometry (HRMS) data was
obtained utilizing electron impact ionization (EI) with a
magnetic sector (EBE trisector), double focusing-geometry
mass analyzer unless indicated otherwise.
H), 2.82 (s, 3H, CH3); C NMR (125 MHz, CDCl ): δ
3
2
00.8 (C=O), 155.2 (Ar-C), 153.6 (Ar-C), 137.5 (Ar-
CH), 136.6 (Ar-C), 133.9 (vinyl CH), 128.9 (Ph-CH),
28.8 (vinyl CH), 127.5 (Ar-C), 127.4 (Ph-CH), 125.3
(Ph-CH), 119.9 (Ar-CH), 25.9 (CH ); IR (ATR-CDCl ):
1
1
-(6-Butyl-pyridin-2-yl)-ethanone (1). R = 0.69, 10%
F
3
3
MTBE:hexanes; MTBE/hexanes (gradient); yellow oil;
isolated yield 0.075 g, 81%; H NMR (500 MHz,
ῡmax = 3032, 3058, 2933, 1697, 1637, 1582, 1562, 1451,
1356, 968, 804, 734, 692, 597 cm ; HRMS (EI): m/z
1
À1
CDCl ): δ 7.83 (dd, J = 7.8, 1.0 Hz, 1H, Ar-H), 7.70 (t,
calculated for C H NO: 223.0997; found: 223.0990.
3
15 13
J = 7.8 Hz, 1H, Ar-H), 7.29 (dd, J = 7.8, 1.0 Hz, 1H, Ar-
H), 2.86–2.83 (m, 2H, CH ), 2.71 (s, 3H, CH ), 1.79–
1
-[6-(2-Cyclohexyl-vinyl)-pyridin-2-yl]-ethanone (9).
2
3
RF
(gradient), brown oil; isolated yield 0.077 g, 59%; H
NMR (500 MHz, CDCl ): δ 7.82 (dd, J = 7.8, 1.0 Hz,
1H, Ar-H), 7.71 (t, J = 7.8 Hz, 1H, Ar-H), 7.39 (dd,
J = 7.8, 1.0 Hz, 1H, Ar-H), 6.82 (dd, J = 15.9, 7.0 Hz,
1H, vinyl H), 6.49 (dd, J = 15.9, 1.2 Hz, 1H, vinyl H),
=
0.71, 10% EtOAc:hexanes; EtOAc/hexanes
1
1
0
.72 (m, 2H, CH ), 1.40 (sextet, J = 7.5 Hz, 2H, CH ),
.97 (t, J = 7.5 Hz, 3H, CH3); C NMR (125 MHz,
2 2
1
3
3
CDCl ): δ 201.1 (C=O), 162.2 (Ar-C), 153.3 (Ar-C),
3
136.9 (Ar-CH), 126.3 (Ar-CH), 118.9 (Ar-CH), 37.9
(
CH ), 31.8 (CH ), 25.9 (CH ), 22.5 (CH ), 14.1 (CH );
2
2
3
2
3
IR (ATR-CDCl ): ῡ
= 3064, 2861, 2958, 2931, 1698,
2.75 (s, 3H, CH ), 2.26–2.17 (m, 1H, CH), 1.89–1.83 (m,
2H, CH ), 1.81–1.67 (m, 2H, CH ), 1.39–1.17 (m, 6H,
3
max
3
À1
1588, 1455, 1357, 907, 732 cm ; HRMS (EI): m/z
2
2
13
calculated for C H NO: 177.1154; found: 177.1152.
11
15
CH × 2); C NMR (125 MHz, CDCl ): δ 200.9 (C=O),
2
3
1
RF
-[6-(3,3-Dimethyl-butyl)-pyridin-2-yl]-ethanone (2).
155.9 (Ar-C), 153.32 (Ar-C), 142.6 (vinyl CH), 137.2
(vinyl CH), 127.0 (Ar-CH), 124.3 (Ar-CH), 119.4 (Ar-
CH), 41.1 (CH), 32.7 (CH ), 26.3 (CH ), 26.1 (CH ),
=
0.73, 10% MTBE:hexanes; MTBE/hexanes
1
(
gradient); yellow oil; isolated yield 0.089 g, 77%; H
2
2
3
NMR (500 MHz, CDCl ): δ 7.83 (d, J = 7.8 Hz, 1H,
Ar-H), 7.70 (t, J = 7.8 Hz, 1H, Ar-H), 7.31 (br-d,
25.8 (CH ); IR (ATR-CDCl ): ῡ
1698, 1651, 1583, 1449, 1356, 970, 800 cm ; HRMS
= 3003, 2924, 2851,
3
2
3
max
À1
J = 7.8 Hz, 1H, Ar-H), 2.85–2.79 (m, 2H, CH ), 2.75
(EI): m/z calculated for C H NO: 229.1467; found:
2
15 19
(
s, 3H, CH ), 1.68–1.62 (m, 2H, CH ), 0.99 (s, 9H,
229.1468.
3
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. E. Lambert and J. D. Carrick
Vol 000
1
-(6-Cyclopropyl-pyridin-2-yl)-ethanone
(10).
(C=O), 156.1 (Ar-C), 153.4 (Ar-C), 149.0 (Ph-C), 148.6
(Ph-C), 137.8 (Ar-CH), 133.0 (Ph-C), 121.1 (Ar-CH),
119.5 (Ar-CH), 108.7 (Ph-CH), 107.5 (Ph-CH), 101.6
RF
gradient); yellow oil; isolated yield 0.041 g, 50%; H
NMR (500 MHz, CDCl ): δ 7.76 (dd, J = 7.7, 1.1 Hz,
=
0.81, 10% EtOAc:hexanes; EtOAc/hexanes
1
(
(CH ), 26.0 (CH ); IR (ATR-CDCl ): ῡ = 3077, 2908,
3
2
3
3
max
1
H, Ar-H), 7.65 (t, J = 7.7 Hz, 1H, Ar-H), 7.32 (dd,
1697, 1582, 1566, 1505, 1458, 1359, 1266, 1250,
À1
J = 7.7, 1.1 Hz, 1H, Ar-H), 2.65 (s, 3H, CH ), 2.11–2.04
802 cm ; HRMS (EI): m/z calculated for C H NO :
3
14 11
3
(
2
1
m, 1H, CH), 1.13–1.08 (m, 2H, CH ), 1.04–0.99 (m,
241.0739; found: 241.0744.
2
13
H, CH2); C NMR (125 MHz, CDCl ): δ 201.0 (C=O),
3
6
-Bromo-pyridine-2-carboxylic acid methoxy-methyl-
62.5 (Ar-C), 153.2 (Ar-C), 136.6 (Ar-CH), 125.1 (Ar-
amide. To a 25 mL round bottom flask equipped with a
magnetic stir bar at ambient temperature was charged 6-
bromo-pyridine-2-carboxylic acid (0.326 g, 1.61 mmol,
1.00 equiv) in anhydrous acetonitrile (3.2 mL, 0.5 M).
The resulting clear solution was treated with
N-methoxy-N-methyl-1H-imidazole-1-carboxamide
CH), 118.2 (Ar-CH), 25.8 (CH ), 17.0 (CH), 10.41
3
(CH ), 10.4X (CH ) overlaps with 10.40; IR (ATR-
2
2
CDCl ): ῡ
8
C H NO: 161.0841; found: 161.0840.
= 3007, 2928, 1698, 1589, 1457, 1356,
3
max
À1
05, 602 cm
;
HRMS (EI): m/z calculated for
1
0
11
1
RF
-(6-Thiophen-2-yl-pyridin-2-yl)-ethanone
(11).
(0.500 g, 3.22 mmol, 2.00 equiv) and allowed to stand at
ambient temperature for fifteen minutes before heating at
80°C for twenty-four hours. The next day the crude
mixture was concentrated under reduced pressure at
ambient temperature to afford a viscous slurry that was
dissolved in MTBE (10 mL) and treated with an aqueous
1 M solution of HCl (5 mL). The organic layer was
separated and the aqueous layer was back-extracted with
(3 × 10 mL) portions of MTBE. The combined organics
were dried over anhydrous Na SO , filtered, and then
=
0.66, 10% EtOAc:hexanes; MTBE/hexanes
(
gradient), yellow amorphous; isolated yield 0.031 g,
0%; H NMR (500 MHz, CDCl ): δ 7.88 (dd, J = 7.0,
.8 Hz, 1H, Ar-CH), 7.82 (t, J = 7.8 Hz, 1H, Ar C-H),
.80 (dd, J = 7.8, 1.8 Hz, 1H, Ar-CH), 7.65 (dd, J = 3.7,
.0 Hz, 1H, Ar -CH), 7.43 (dd, J = 5.0, 1.0 Hz, 1H, Ar -
CH), 7.14 (dd, J = 5.0, 3.7 Hz, 1H, Ar -CH), 2.79 (s, 3H,
CH3); C NMR (125 MHz, CDCl ): δ 200.4 (C=O),
53.3 (Ar-C), 152.1 (Ar-C), 144.4 (Ar -C), 137.7 (Ar-
1
3
1
7
1
3
t
t
t
13
3
1
t
2
4
CH), 128.4 (Ar-CH), 128.3 (Ar -CH), 125.3 (Ar -CH),
concentrated under reduced pressure at ambient
temperature to afford a crude semisolid which was
absorbed on neutral alumina and purified using
automated flash-column chromatography with an
EtOAc/hexanes gradient, including a 20% isocratic hold,
t
t
1
22.0 (Ar -CH), 119.7 (Ar-CH), 25.8 (CH ); IR (ATR-
t
3
CDCl ): ῡ
= 3073, 2928, 1698, 1582, 1455, 1359,
3
max
À1
1298, 1243, 806, 707, 593 cm ; HRMS (EI): m/z
calculated for C H NOS: 203.0405; found: 203.0410.
11 9
to afford the title compound as a clear liquid (0.194 g,
1
-[2,3’]Bipyridinyl-6-yl-ethanone (12). R = 0.16, 50%
F
1
5
3%) [26]; R = 0.24, 30% EtOAc:hexanes; H NMR
EtOAc:hexanes; EtOAc/hexanes (gradient), brown oil;
isolated yield 0.094 g, 93%; H NMR (500 MHz,
F
1
(
500 MHz, CDCl ): δ 7.64 (t, J = 7.3 Hz, 1H, Ar-H),
3
CDCl ): δ 9.31 (br-s, 1H, Ar-H), 8.69 (br-d, J = 4.8 Hz,
7.62–7.57 (m, 1H, Ar-H), 7.55 (d, J = 8.7 Hz, 1H, Ar-H),
3.80 (br-s, 3H, OCH ), 3.36 (br-s, 3H, CH ); IR (ATR-
3
1
8
H, Ar-H), 8.40 (ddd, J = 7.8, 2.4, 1.7 Hz, 1H, Ar-H),
.03 (dd, J = 5.9, 3.1 Hz, 1H, Ar-H), 7.95–7.93 (m, 2H,
3
3
CDCl
): ῡmax = 3080, 2977, 2935, 1658, 1578, 1408,
3
À1
Ar-H × 2), 7.44 (ddd, J = 7.8, 4.8, 0.8 Hz, 1H, Ar-H),
1381, 1123, 988, 811, 753 cm ; HRMS (EI): m/z
calculated for C
found: 212.9654.
1
3
+
2
.81 (s, 3H, CH3); C NMR (125 MHz, CDCl ): δ 200.3
H
8
BrN
9
O
2
2
[m À OCH
3
] : 212.9663;
3
(
1
C=O), 154.1 (Ar-C), 153.8 (Ar-C), 150.5 (Ar-CH),
48.5 (Ar-CH), 138.1 (Ar-CH), 134.4 (Ar-C), 134.0 (Ar-
C), 123.8 (Ar-CH), 123.6 (Ar-CH), 120.7 (Ar-CH), 25.9
[
2,3’]Bipyridinyl-6-carbonitrile (14). R = 0.20, 70%
F
EtOAc:hexanes; EtOAc/hexanes (gradient), yellow solid;
1
(
1
CH ); IR (ATR-CDCl ): ῡ
453, 1438, 1357, 1311, 798, 707, 595 cm ; HRMS
= 3011, 2927, 1698, 1586,
3
3
max
mp = 70.9–72.8°C; isolated yield 0.088 g, 41%; H NMR
À1
(
500 MHz, CDCl ): δ 9.23 (d, J = 2.3 Hz, 1H, Ar-H),
3
(
EI): m/z calculated for C H N O: 198.0793; found:
12 10 2
8.73 (dd, J = 5.0, 1.0 Hz, 1H, Ar-H); 8.47–8.44 (m, 1H,
Ar-H); 8.00 (dt, J = 8.0, 1.0 Hz, 1H, Ar-H), 7.97 (t,
J = 8.0 Hz, 1H, Ar-H), 7.71 (dd, J = 7.4, 1.0 Hz, 1H, Ar-
198.0797.
1
-(6-Benzo[1,3]dioxol-5-yl-pyridin-2-yl)-ethanone (13).
13
RF
=
0.49, 10% EtOAc:hexanes; EtOAc/hexanes
H), 7.50 (dd, J = 8.0, 5.0 Hz, 1H, Ar-H); C NMR
(125 MHz, CDCl ): δ 156.2 (Ar-C), 150.5 (Ar-CH),
(
gradient), white solid; mp = 145.3–147.8°C; isolated
3
1
yield 0.098 g, 77%; H NMR (500 MHz, CDCl ): δ 7.91
147.7 (Ar-CH), 138.4 (Ar-CH), 135.4 (Ar-CH), 134.5
(Ar-C), 133.3 (Ar-C), 127.6 (Ar-CH), 124.2 (Ar-CH),
123.6 (Ar-CH), 117.7 (RCN); IR (ATR-CDCl3):
ῡmax = 3068, 2977, 2932, 2239, 1696, 1586, 1519, 1450,
3
(dd, J = 7.1, 1.6 Hz, 1H, Ar-H), 7.84 (t, J = 7.1 Hz, 1H,
Ar-H), 7.80 (dd, J = 7.8, 1.6 Hz, 1H, Ar-H), 7.65 (d,
J = 1.6 Hz, 1H, Ph-H), 7.58 (dd, J = 8.2, 1.6 Hz, 1H, Ph-
À1
H), 6.92 (d, J = 8.2 Hz, 1H, Ph-H), 6.03 (s, 2H, CH ),
1437, 1394, 1023, 798, 707, 736 cm ; HRMS (EI): m/z
2
1
3
2
.78 (s, 3H, CH3); C NMR (125 MHz, CDCl ): δ 200.8
calculated for C H N : 181.0640; found: 181.0647.
11 7 3
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthetic Access to Functionalized 2-carbonyl and Procarbonyl
Pyridine Synthons
13
6
-(2-p-Tolyl-vinyl)-pyridine-2-carbaldehyde
(15).
3.46 (br-s, 3H, OCH ); 2.37 (s, 3H, CH ); C NMR
3 3
RF
=
0.72, 30% EtOAc:hexanes; EtOAc/hexanes
(125 MHz, CDCl ): δ 165.6 (C=O), 155.0 (Ar-C), 139.0
3
1
(gradient); pale-yellow solid; mp = 100.1–101.2°C; H
(Ar-CH), 138.8 (Ar-C), 137.3 (Ar-CH), 133.81 (vinyl
CH), 133.78 (vinyl CH), 129.7 (Ph-C), 129.7 (Ph-CH),
127.3 (Ph-CH), 126.6 (Ar-CH), 122.8 (Ph-C), 61.7
(OCH ), 26.3 (CH ), 21.5 (CH ); IR (ATR-CDCl ):
NMR (500 MHz, CDCl ): δ 10.13 (s, 1H, RCHO), 7.83
3
(t, J = 7.5 Hz, 1H, Ar-H), 7.81 (dt, J = 7.8, 1.2 Hz, 1H,
Ar-H), 7.74 (d, J = 16.2 Hz, 1H, vinyl H), 7.60 (dd,
J = 7.5, 1.2 Hz, 1H, Ar-H), 7.52 (d, J = 8.1 Hz, 2H, Ph-
H), 7.21 (d, J = 8.1 Hz, 2H, Ph-H), 7.20 (d, J = 16.2 Hz,
3
3
3
3
ῡmax = 3031, 2973, 2934, 1652, 1583. 1564, 1513, 1451,
À1
1
382, 990, 821, 751 cm ; HRMS (EI): m/z calculated
1
3
1H, vinyl H), 2.39 (s, 3H, CH3); C NMR (125 MHz,
for C H N O : 282.1368; found: 282.1359.
17 18 2 2
CDCl ): δ 194.0 (RCHO), 156.7 (Ar-C), 152.7 (Ar-C),
3
6
-Phenethyl-pyridine-2-carbonitrile (20).
RF = 0.45,
1
(
1
39.1 (Ph-C), 137.7 (vinyl CH), 134.6 (vinyl CH), 133.6
Ph-C), 129.7 (Ph-CH), 127.4 (Ph-CH), 125.9 (Ar-CH),
25.8 (Ar-CH), 119.8 (Ar-CH), 21.5 (CH ); IR (ATR-
1
0%
EtOAc:hexanes;
EtOAc/hexanes
(gradient),
1
amorphous; isolated yield 0.082 g, 63%; H NMR
3
(
500 MHz, CDCl ): δ 7.67 (t, J = 7.8 Hz, 1H, Ar-H),
3
CDCl ): ῡ
= 3031, 2824, 1708, 1638, 1582, 1453,
3
max
7
.53 (dd, J = 7.8, 0.9 Hz, 1H, Ar-H), 7.29–7.22 (m, 3H,
À1
1512, 971, 909, 815, 732 cm ; HRMS (EI): m/z
Ar-H, Ph-H); 7.21–7.15 (m, 3H, Ph-H, Ph-H); 3.17–3.13
calculated for C H NO: 223.0997; found: 223.0988.
15
13
13
(
(
(
m, 2H, CH ); 3.09–3.04 (m, 2H, CH ); C NMR
2 2
6
-(4-Methoxy-phenyl)-pyridine-2-carboxylic
acid
125 MHz, CDCl ): δ 163.5 (Ar-C), 140.9 (Ar-C), 137.1
Ar-CH), 133.6 (Ph-C), 128.59 (Ph-CH), 128.5X (Ph-
3
methoxy-methyl-amide (16).
RF = 0.46, 70%; EtOAc:
hexanes;
isolated yield 0.044 g, 22%; H NMR (500 MHz,
CDCl3): 8.01–7.97 (m, 2H, Ph-H), 7.81 (t,
J = 7.4 Hz, 1H, Ar-H), 7.75 (br-d, J = 8.5 Hz, 1H,
Ar-H), 7.52 (br-s, 1H, Ar-H), 7.04–6.97 (m, 2H, Ph-
H), 3.87 (s, 3H, OCH ), 3.81 (br-s, 3H, OCH ), 3.49
EtOAc/hexanes
(gradient);
amorphous;
1
CH) overlaps with 128.59, 126.7 (Ar-CH), 126.3 (Ph-H),
26.2 (Ar-CH), 117.6 (CN), 39.9 (CH ), 35.5 (CH ); IR
1
2
2
δ
(
1
ATR-CDCl ): ῡ
587, 1568, 1497, 1451, 802, 751, 699 cm ; HRMS
= 3063, 3027, 2928, 2862, 2236,
3
max
À1
+
(
EI): m/z calculated for C H N [m À H] : 207.0917;
14 12 2
3
3
13
found: 207.0918.
(s, 3H, CH3); C NMR (125 MHz, CDCl ): δ 171.3
3
(C=O), 160.8 (Ph-C), 155.9 (Ar-C), 153.3 (Ar-C),
1
(
37.5 (Ar-CH), 131.4 (Ph-C), 128.4 (Ph-CH), 120.8
Ar-CH), 114.27 (Ph-CH), 114.2X (Ar-CH) (overlaps
with 114.27), 60.5 (OCH ), 55.5 (OCH ), 38.8 (CH );
Acknowledgments. This work was supported by the Tennessee
Board of Reagents Office of Academic Affairs Faculty Research
Grant program and the Tennessee Technological University
Department of Chemistry. Ryan P. Downs is acknowledged for
the initial preparation of compounds 2 and 20. Support from
National Science Foundation (NSF) Major Research
Instrumentation (MRI) 1531870 is gratefully acknowledged for
the acquisition of the university’s 500 MHz multi-nuclear NMR
spectrometer. Dr. Qiaoli Liang, The University of Alabama, is
gratefully acknowledged for acquisition of HRMS data.
3
3
3
IR (ATR-CDCl ): ῡ
2
= 3007, 2977, 2936, 2903,
3
max
841, 1652, 1609, 1566, 1516, 1384, 1310, 1296,
À1
1179, 1030, 821, 732, 583 cm ; HRMS (EI): m/z
calculated for C H N O : 272.1161; found: 272.1166.
15 16 2 3
6
-(4-tert-Butyl-phenyl)-pyridine-2-carbonitrile (18).
RF
=
0.62, 30% EtOAc:hexanes; EtOAc/hexanes
(gradient), yellow amorphous; isolated yield 0.077 g,
1
6
8%; H NMR (500 MHz, CDCl ): δ 7.99–7.95 (m, 2H,
3
Ph-H), 7.96 (br-dd, J = 8.1, 1.0 Hz, 1H, Ar-H), 7.86 (t,
J = 7.8 Hz, 1H, Ar-H), 7.60 (br-d, J = 7.8 Hz, 1H, Ar-
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13
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2
1
1
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(
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1
conversion of starting material by H NMR was over 95%. Employment
[
[
of neutral alumina stationary phase afforded improved purification
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[26] This compound is susceptible to rapid degradation and the end
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possible. Attempted azeotropic removal of residual solvents from chroma-
[
tography using CHCl
hold times in deuterated solvents (CDCl , C D , or CD OD) for C NMR
3 6 6 3
, C H , or CH OH resulted in degradation. Extended
13
2
3 6 6 3
[
also resulted in substantial degradation. Removal of residual solvents under
vacuum using the freeze, pump, thaw technique was also unsuccessful.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet