Cu-Catalyzed Three-Component Cascade Annulation Reaction: An Entry to Functionalized Pyridines

Article abstract of DOI:10.1021/acs.joc.5b01621

A concise copper-catalyzed N-O bond cleavage/C-C/C-N bond formation procedure has been described for the synthesis of multisubstituted pyridines. Various oxime acetates, activated methylene compounds, and a wide range of aldehydes bearing aryl, heteroaryl, vinyl, and trifluoromethyl groups were employed to provide the tri- or tetrasubstituted pyridines with flexible substitution patterns. Moreover, this method features inexpensive catalysts, no need for extra oxidant, and high step-enconomy, which make it pratical and attractive.

Full text of DOI:10.1021/acs.joc.5b01621

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Article
Cu-Catalyzed Three-Component Cascade Annulation
Reaction: An Entry to Functionalized Pyridines
Huanfeng Jiang, Jidan Yang, Xiaodong Tang, Jiaoxiao Li, and Wanqing Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01621 • Publication Date (Web): 19 Aug 2015
Downloaded from http://pubs.acs.org on August 19, 2015
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Cu-Catalyzed Three-Component Cascade Annulation
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Reaction: An Entry to Functionalized Pyridines
Huanfeng Jiang*, Jidan Yang, Xiaodong Tang, Jianxiao Li, and Wanqing Wu
School of Chemistry and Chemical Engineering, South China University of Technology,
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Guangzhou 510640, China
Fax: (+86) 20ꢀ8711ꢀ2906; Eꢀmail: jianghf@scut.edu.cn
Abstract: A concise copperꢀcatalyzed N–O bond cleavage/C–C/C–N bonds formation
procedure has been described for the synthesis of multisubstituted pyridines. Various
oxime acetates, activated methylene compounds, and a wide range of aldehydes
bearing aryl, heteroaryl, vinyl and trifluoromethyl groups were employed to provide
the triꢀ, or tetrasubstituted pyridines with flexible substitution pattern. Moreover, this
method features inexpensive catalysts, no need of extra oxidant and high
stepꢀenconomy, which make it pratical and attractive.
INTRODUCTION
Pyridine skeletons are a class of important azaheterocyclic structure as the naturally
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occurring bioactive compounds,1 pharmaceutical molecules,2 and the fundamental
part of ligands, intermediates, and building blocks in polysubstituted form3. For
example, 3ꢀpyridinecarboxamide derivative (nicotinamide ‘vitamin B3’) is widely
applied in clinical practice to treat pellagra and some neurodegenerative diseases.4
Therefore, the synthesis of pyridines has received intensive attention and encouraged
the development of more valuable synthetic strategies.5 Traditionally, pyridine
synthesis relies on the condensation of amine and carbonyl compounds, including
[5+1] condensation of 1,5ꢀdicarbonyls with ammonia (NH3), [2+2+1+1] Hantzsch
pyridine synthesis and [3+3] cyclzation of 1,3ꢀdicarbonyl derivatives with vinylogous
amides.6 Recently, tremendous effort has been made in the field of transition
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metalꢀcatalyzed cyclizations and crossꢀcoupling reactions to afford functionalized
pyridine derivatives.7 For example, rhodium catalyzedꢀ[4+2] cycloaddition reaction
for the formation of pyridine derivatives from alkynes and α,βꢀunsaturated imines has
been achieved by Ellman and Cheng et al.7i, 7j Despite the synthetic efficiency of these
methods, unstable nature of the precursors, expensive noble metal catalysts, and
tedious operations directly limited the regioselectivity and functional diversity to
afford some practical and sensitive pyridines. Thereforoe, it still remains highly
desirable to develop versatile and highly chemoꢀ and regioselective strategies starting
from easily available reagents for the construction of pyridine rings under mild
conditions with more flexible substitution patterns.
On the other hand, oxime derivatives using as internal oxidants have been proved
to be an extremely effective method for constructing Nꢀcontaining heterocycles by
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transition metal catalysis, including ruthenium,8 rhodium,9 palladium,10 and copper11.
Recently, advancements in copperꢀcatalyzed cyclization of oxime esters offer new
routes to the synthesis of pyridine derivatives.12 Notably, Yoshikai and coꢀworkers
described a synergistic copper/iminiumꢀcatalyzed strategy to construct pyridines from
oximes and enals.12b In particular, copperꢀcatalyzed threeꢀcomponent cascade
annulations with the participation of oxime esters have emerged as pratical and
convenient approaches to functionalized pyridines, which provided simpler and
convergent accesses to pyridine frameworks with diverse substitution patterns in a
oneꢀpot from easily accessible reagents.13 During the interests of our studies in
copperꢀcatalyzed coupling of ketoxime esters, the preparation of sulfone derivatives
and a series of functionalized Nꢀcontaining heteropolycycles have been successfully
accessed.14, 11aꢀd Very rencently, we have developed a practical protocol for various
substituted pyrazoles via copperꢀcatalyzed cascade reactions of oxime acetates,
amines, and aldehydes (Scheme 1a).11d Inspired by these precedents, we conceived
that the Cuꢀcatalyzed NꢀO bond cleavage, CꢀC/CꢀN bond formation and oxidative
dehydrogenation process could occur in an oneꢀpot manner. Herein, we present our
recent progress in a Cu(I)ꢀcatalyzed multicomponent cascade annulation strategy with
oxime acetates, activated methylene compounds, and aldehydes for the construction
of triꢀ, and tetrasubstituted pyridines (Scheme 1b).
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Scheme 1. Synthesis of Nꢀcontaining heterocycles via Cuꢀcatalyzed threeꢀcomponent
reactions with the participation of oxime esters
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RESULTS AND DISCUSSION
Initially, the project was carried out by investigating the reaction of acetophenone
oxime acetate (1a), paraformaldehyde (2) and ethyl acetoacetate (3a) in the presence
of CuI and Cs2CO3 (Table 1). To our delight, the combination of CuI and DMSO
under N2 atmosphere afforded the desired product 4a in 58% yield (Table 1, entry 1).
Associating with previous works, the base was proved to be crucial to the interaction
between copper(I) salts and oxime esters.11a, 11b, 12b, 14 As revealed in Table 1, the other
bases such as Li2CO3, NaHSO3, Et3N, DBU, and tꢀBuOK were investigated (entries
2ꢀ6), and Li2CO3 was found to be optimal, giving 4a in 68% yield (entry 2).15 The
absence of base was ineffective for this transformation (entry 7). As expected, no
product was observed without copper salts (entry 8). Subsequently, different copper
salts were examined, including CuCl, CuBr, CuBr2, Cu(OAc)2 and Cu(OTf)2,
obtaining 4a in the yields of 67%, 74%, 42%, 59% and 56%, respectively (Table 1,
entries 9ꢀ13), and CuBr was the most effective catalyst for this transformation (entry
10).15 Replacing DMSO with other solvents, such as DMF, toluene, DCE or CH3CN
did not improve the yields of the desired product (entries 14ꢀ17). Thus, the optimized
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catalytic system for this cascade annulation reaction was: 1a (0.3 mmol), 2 (0.3
mmol), 3a (1.5 equiv), CuBr (10 mol %), Li2CO3 (20 mol %) in DMSO at 120 oC
under N2 for 6 h.
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Table 1. Optimization of the reaction conditionsa
Yield (%)b
Entry
1
Catalyst
CuI
Base
Cs2CO3
Li2CO3
NaHSO3
Et3N
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
58
2
CuI
68
60
61
57
59
27
0
3
CuI
4
CuI
5
CuI
DBU
6
CuI
tꢀBuOK
none
7
CuI
8
none
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
9
CuCl
CuBr
CuBr2
Cu(OAc)2
Cu(OTf)2
CuBr
CuBr
CuBr
CuBr
67
74
42
59
56
63
25
26
33
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17
Toluene
DCE
CH3CN
a Unless otherwise noted, all reactions were performed with 1a (0.3 mmol), 2 (0.3 mmol), 3a (1.5
equiv), catalyst (10 mol %), base (20 mol %) and solvent (2 mL) at 120 oC under N2 atmosphere
for 6 h.b Determined by GC using dodecane as an internal standard.
On the basis of the optimized reaction conditions, various activated methylene
compounds were investigated for the preparation of 2,3,5ꢀtrisubstituted pyridines.
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Representative results are summarized in Table 2. Pleasingly, various substituted
βꢀketo esters exhibited good functionalꢀgroup tolerance to afford the desired products
with high chemoselectivity in moderate to excellent yields (4a-4f). When
acetylacetone (3g) and dibenzoylmethane (3i) were employed, the corresponding
pyridine derivatives 4g and 4i were successfully obtained in 84% and 80% yields,
respectively. Moreover, the unsymmetrical 1,3ꢀdiketone 3h could be also efficiently
transferred to the desired product with good regioselectivity. And the structure of 4h
has been confirmed by singleꢀcrystal Xꢀray analysis.16 Notably, this strategy was
available for the construction of nicotinamide derivatives 4j and 4k in reasonable
yields, which have shown strong biological activity.4 Additionally,
1ꢀtosylpropanꢀ2ꢀone (3l) was also compatible in this transformation and gave the
corresponding product 4l in 67% yield.
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Table 2. Substrate scope of various activated methylene compounds 3a
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R2
EWG
5
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8
NOAc
+
N
CuBr (10 mol %)
O
Li2CO3 (20 mol %)
EWG
+
(CH2O)n
R2
DMSO, 120 oC, N2
4
2
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1a
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O
O
O
O
N
O
N
O
N
O
N
O
4d, 63 %
4b, 76%
4c, 73 %
4a, 71 %
O
O
O
O
N
O
N
O
N
N
4g, 84 %
4h, 78 %
4e, 81 %
4f, 78 %
O
O
N
O
O
S
N
N
H
N
N
N
O
4i, 80 %
4j, 57%
4l, 67 %
4k, 64%
a
All reactions were performed with 1a (0.3 mmol), 2 (0.3 mmol), 3 (1.5 equiv), Li2CO3 (20
mol %), CuBr (10 mol %) in DMSO (2 mL) at 120 °C under N2 atmosphere for 6 h.
Table 3. Substrate scope of various oxime acetates 1a
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a
Reaction conditions: all reactions were performed with 1 (0.3 mmol), 2 (0.3 mmol), 3g (1.5
equiv), Li2CO3 (20 mol %), CuBr (10 mol %) in DMSO (2 mL) at 120 °C under N2 atmosphere
for 6 h.
Scheme 2. Synthesis of pridine derivatives derived from natural product core
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Table 4. Substrate scope of various aldehydes 6 a
a
All reactions were performed with 1a (0.3 mmol), 6 (0.3 mmol), 3g (1.5 equiv), Li2CO3 (20
mol %), CuBr (10 mol %) in DMSO (2 mL) at 120 °C under N2 atmosphere for 6 h.
With the positive results above, we set out to evaluate the generality of different
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ketone oxime acetates under the optimal reaction conditions (Table 3). A series of
phenylethanone oxime acetates with an electronꢀdonating or electronꢀwithdrawing
substituent on the arene functionality successfully participated in this transformation,
providing the desired products in satisfactory yields (5a-5h). 1ꢀPhenylhexanꢀ1ꢀone
and 1,2ꢀdiphenylethanꢀ1ꢀone also proceeded smoothly to afford the
2,3,5,6ꢀtetrasubstituted pyridines in 52% and 81% yields, respectively (5i and 5j).
Moreover, when polysubstituted oxime ester with a cyclic scaffold was employed, the
polycyclic pyridine 5k was successfully obtained in 67% yield. Notably, the
introduction of furan, thiophene and pyridine heterocycle into this system made this
process more useful for the preparation of practical products (5l-5o). Besides, even if
a series of aliphatic ketone oxime acetates were used, the reasonable yields were also
obtained (5p-5s). Gratifyingly, oximes derived from cyclic aliphatic ketones such as
cyclopentanone, cyclohexanone, cycloheptanone, and cyclooctanone were performed
well to generate the corresponding dicyclic products in the yields of 62%, 69%, 81%
and 82%, respectively (5t-5w). Unfortunately, oxime esters with cyclopropanone and
cyclobutanone were failed to transfer into the corresponding products under the
optimized conditions, which indicated that ring strain effects affected this
transformation.
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Under the optimal reaction conditions, it is delightful that oximes derived from
L(ꢀ)ꢀCarvone and βꢀIonone smoothly participated in the transformation, affording the
corresponding pyridineꢀskeleton molecules containing natural product core in
reasonable yields, respectively (Scheme 2, 5x and 5y).
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In addition to paraformaldehyde, other aldehydes were found to be favored to
afford the 2,3,4,6ꢀtetrasubstituted pyridines with high efficiencies and the results are
summarized in Table 4. Satisfactorily, benzaldehydes with a series of valuable
functional groups, such as methyl, methoxyl, halogen, cyano, nitro, and aldehyde,
were successfully transferred to the desired products in moderate to excellent yields
(7a-7h). Additionally, heteroaromatic aldehydes with furan, thiophene, and pyridine
skeletons exhibited similar reactivity with benzaldehydes, affording the annulation
products in good yields (7i-7k). The transformation of transꢀcinnamaldehyde could
proceed smoothly to give substituted pyridines 7l in moderate yields. It is noteworthy
that trifluoromethyl substituted pyridines 7m could be separated in 27% yield when
trifluoroacetaldehyde hydrate was used.17
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Scheme 3. Investigation of the reaction mechanism a
To get the deep insight of the mechanism of this tranformation, we performed the
reaction of benzaldehyde 6a and acetylacetone 3g under the standard conditions, and
3ꢀbenzylidenepentaneꢀ2,4ꢀdione B was obtained in 77% yield. Notably, when we
coupled oxime acetate 1a with compound B, the desired product 7a was formed in
excellent yield (Scheme 3). Based on the above results and previous studies on oxime
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derivatives,11ꢀ14, 18 the plausible mechanism for this cascade annulation reaction is
illustrated in Scheme 4. Firstly, the cleavage of the NꢀO bond of 1 is initiated by
copper salts, generating copper enamide intermediate A and producing another CuII
species.11a, 11d, 14 Subsequently, the nucleophilic addition of copper(II) enamide
complex A to intermediate B gives the imine intermediate C,13 the tautomer of D.
Then the intramolecular nucleophile attack affords the dihydropridine complex E.
Finally, the target product is generated from oxidation of intermediate E by Cu(II)
species and regeneration of Cu(I).
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Scheme 4. Proposed mechanism
CONCLUSION
In conclusion, we have developed a Cuꢀcatalyzed threeꢀcomponent cascade reaction
for the synthesis of polysubstituted pyridines with high variability and impressive
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selectivity from ketoxime acetates, aldehydes and activated methylene compounds
under mild conditions. In this procedure, a oneꢀpot, fourꢀstep tandem cascade
annulation process was described, which has provided a potential strategy for the
preparation of more complex and significant pharmaceuticals. Notablely, this
transformation successfully extends its application to construct bipyridine,
nicotinamide derivatives and attractive structures containing L(ꢀ)ꢀCarvone and
βꢀIonone natural scaffolds.
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EXPERIMENTAL SECTION
General methods. Melting points were measured by a melting point instrument and
were uncorrected. 1H and 13C NMR spectra were recorded by using a 400 MHz NMR
1
spectrometer. H and 13C NMR spectra are reported in parts per million (ppm)
downfield from an internal standard, tetramethylsilane (0 ppm) and CHCl3 (77.0 ppm),
respectively. IR spectra were obtained either as potassium bromide pellets or as liquid
films between two potassium bromide pellets with an infrared spectrometer. GCꢀMS
was obtained using electron ionization. The data of HRMS was carried out on a
highꢀresolution mass spectrometer (LCMSꢀITꢀTOF). Unless otherwise noted, all
purchased chemicals were used without further purification. The ketoxime acetates
were prepared according to the literature.9a, 14
General Procedure for the Synthesis of Polysubstituted Pyridines 4, 5 and 7. The
ketoxime acetates 1 (0.3 mmol), aldehydes 2 or 6 (0.3 mmol), activated methylene
compound 3 (1.5 equiv), CuBr (10 mol %, 0.03 mmol, 4.26 mg) and Li2CO3 (20
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mol %, 0.06 mmol, 4.44 mg) were stirred in DMSO (2.0 mL) at 120 °C, in a 20 mL
tube under N2 for 6 h. When the reaction was completed (detected by TLC), the
mixture was cooled to room temperature. The reaction was quenched with H2O (10
mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried
over anhydrous MgSO4 and then evaporated in vacuum. The residue was purified by
column chromatography on silica gel to afford the corresponding pyridines with
hexanes/ethyl acetate as the eluent.
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Ethyl 2-Methyl-6-phenylnicotinate (4a): Yield: 71% (51.3 mg) as a yellow oil; 1H
NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.61 (d,
J = 8.2 Hz, 1H), 7.49ꢀ7.41 (m, 3H), 4.39 (q, J = 7.2 Hz, 2H), 2.92 (s, 3H), 1.41 (t, J =
13
7.2 Hz, 3H); C {1H} NMR (100 MHz, CDCl3) δ 166.6, 159.9, 159.0, 139.3, 138.5,
129.7, 128.8, 127.3, 123.7, 117.3, 61.1, 25.3, 14.3; IR (KBr): 2982, 1719, 1585, 1540,
1268, 1085, 757, 694 cm−1; MS (EI) m/z 77, 83, 115, 141, 168, 196, 213, 241;
HRMSꢀESI (m/z): calcd for C15H16NO2, [M+H]+ : 242.1176, found, 242.1182.
Methyl 2-Methyl-6-phenylnicotinate (4b): Yield: 76% (51.8 mg) as a yellow oil; 1H
NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 6.8 Hz, 2H), 7.61 (d,
J = 9.8 Hz, 1H), 7.50ꢀ7.42 (m, 3H), 3.93 (s, 3H), 2.93 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3) δ 167.0, 160.1, 159.2, 139.4, 138.4, 129.7, 128.8, 127.3, 123.3, 117.4,
52.2, 25.2; IR (KBr): 2952, 1726, 1585, 1432, 1272, 1090, 758, 693 cm−1; MS (EI)
m/z 77, 83, 115, 141, 168, 196, 212, 227; HRMSꢀESI (m/z): calcd for C14H14NO2,
[M+H]+ : 228.1019, found, 228.1025.
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Allyl 2-Methyl-6-phenylnicotinate (4c): Yield: 73% (55.4 mg) as a yellow oil; H
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NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 7.2 Hz, 2H), 7.62 (d,
J = 8.2 Hz, 1H), 7.50ꢀ7.42 (m, 3H), 6.11ꢀ6.01 (m, 1H), 5.43 (d, J = 17.2 Hz, 1H), 5.32
(d, J = 10.4 Hz, 1H), 4.84 (d, J = 5.6 Hz, 2H), 2.94 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3) δ 166.2, 160.2, 159.2, 139.4, 138.4, 132.1, 129.7, 128.8, 127.3, 123.3,
118.6, 117.4, 65.8, 25.3; IR (KBr): 3067, 2936, 1723, 1548, 1449, 1263, 1075, 757,
695 cm−1; MS (EI) m/z 77, 83, 115, 141, 153, 168, 184, 196, 212, 253; HRMSꢀESI
(m/z): calcd for C16H16NO2, [M+H]+ : 254.1176, found, 254.1181.
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tert-Butyl 2-Methyl-6-phenylnicotinate (4d): Yield: 63% (50.8 mg) as a yellow oil;
1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 7.2 Hz, 2H), 7.58
(d, J = 8.2 Hz, 1H), 7.50ꢀ7.41 (m, 3H), 2.89 (s, 3H), 1.61 (s, 9H); 13C {1H} NMR
(100 MHz, CDCl3) δ 166.1, 159.3, 158.6, 139.2, 138.6, 129.5, 128.8, 127.3, 125.4,
117.4, 81.8, 28.3, 25.3; IR (KBr): 2977, 2931, 1715, 1584, 1452, 1369, 1285, 1143,
848, 758 cm−1; MS (EI) m/z 77, 83, 115, 141, 168, 196, 213, 269; HRMSꢀESI (m/z):
calcd for C17H20NO2, [M+H]+ : 270.1489, found, 270.1492.
Benzyl 2-Methyl-6-phenylnicotinate (4e): Yield: 81% (73.6 mg) as a yellow solid;
mp = 61.4ꢀ62.7 oC; 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.2 Hz, 1H), 8.02 (d, J
= 6.8 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.43ꢀ7.40 (m, 4H), 7.38 (d, J = 6.8 Hz, 2H),
7.35ꢀ7.31 (m, 2H), 5.33 (s, 2H), 2.91 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ
166.3, 160.3, 159.2, 139.5, 138.4, 135.9, 129.8, 128.9, 128.7, 128.5, 128.4, 127.4,
123.3, 117.4, 67.0, 25.4; IR (KBr): 3064, 3023, 2952, 1724, 1586, 1455, 1381, 1092,
1066, 756, 695 cm−1; MS (EI) m/z 65, 77, 91, 115, 141, 168, 196, 226, 258, 303;
HRMSꢀESI (m/z): calcd for C20H18NO2, [M+H]+ : 304.1332, found, 304.1338.
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Ethyl 2,6-Diphenylnicotinate (4f): Yield: 78% (70.9mg) as a yellow oil; H NMR
(400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 6.8 Hz, 2H), 7.78 (d, J =
8.0 Hz, 1H), 7.66 (d, J = 5.6 Hz, 2H), 7.50 (d, J = 6.8 Hz, 2H), 7.47 (d, J = 4.0 Hz,
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2H), 7.45 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.08 (t, J = 7.1 Hz, 3H); C {1H} NMR
(100 MHz, CDCl3) δ 168.3, 158.8, 158.4, 140.6, 138.9, 138.3, 129.8, 128.9, 128.8,
128.6, 128.0, 127.4, 125.4, 117.9, 61.4, 13.7; IR (KBr): 3061, 2929, 2853, 1717, 1582,
1436, 1380, 1291, 1144, 762, 696 cm−1; MS (EI) m/z 65, 77, 91, 115, 141, 168, 196,
226, 258, 303; HRMSꢀESI (m/z): calcd for C20H18NO2, [M+H]+ : 304.1332, found,
304.1334.
1-(2-Methyl-6-phenylpyridin-3-yl)ethan-1-one (4g): Yield: 84% (53.2 mg) as a
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yellow solid; mp = 90.3ꢀ91.5 C; H NMR (400 MHz, CDCl3) δ 8.05 (t, J = 7.4 Hz,
3H), 7.63 (d, J = 8.0 Hz, 1H), 7.50ꢀ7.43 (m, 3H), 2.85 (s, 3H), 2.61 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3) δ 199.9, 158.6, 158.6, 138.4, 138.0, 130.7, 129.8, 128.9,
127.3, 117.3, 29.3, 25.3; IR (KBr): 2965, 2927, 1682, 1583, 1555, 1457, 1260, 743,
692 cm−1; MS (EI) m/z 77, 83, 115, 141, 153, 168, 184, 196, 211; HRMSꢀESI (m/z):
calcd for C14H14NO, [M+H]+ : 212.1070, found, 212.1074;
1-(2,6-Diphenylpyridin-3-yl)ethan-1-one (4h): Yield: 78% (63.9 mg) as a yellow
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solid; mp = 75.1ꢀ76.4 C; H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 2H),
7.83 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.65ꢀ7.60 (m, 2H), 7.51ꢀ7.45 (m,
5H), 2.64 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 197.2, 158.1, 157.0, 138.7,
137.4, 137.3, 133.5, 130.0, 129.5, 128.9, 128.7, 127.2, 116.9, 23.8; IR (KBr): 3061,
2925, 2852, 1663, 1581, 1448, 1275, 933, 747, 694 cm−1; MS (EI) m/z 77, 105, 141,
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153, 168, 184, 196, 244, 273; HRMSꢀESI (m/z): calcd for C19H16NO, [M+H]+ :
274.1226, found, 274.1230.
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(2,6-Diphenylpyridin-3-yl)(phenyl)methanone (4i): Yield: 80% (80.4 mg) as a
yellow solid; mp = 101.4ꢀ103.1 oC; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.2 Hz,
2H), 7.90 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.2 Hz, 2H), 7.62
(d, J = 6.8 Hz, 2H), 7.49 (t, J = 7.2 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6
Hz, 1H), 7.27 (t, J = 7.3 Hz, 2H), 7.23 (d, J = 7.2 Hz, 3H); 13C {1H} NMR (100 MHz,
CDCl3) δ 197.50, 158.04, 157.29, 139.54, 138.44, 138.32, 136.90, 133.26, 132.62,
129.89, 129.75, 129.49, 128.89, 128.38, 128.28, 127.32, 117.88; IR (KBr): 3060,
1663, 1432, 1314, 1279, 927, 749, 695 cm−1; MS (EI) m/z 77, 105, 128, 167, 202, 228,
258, 306, 335; HRMSꢀESI (m/z): calcd for C24H18NO, [M+H]+ : 336.1383, found,
336.1386.
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N,2-Dimethyl-6-phenylnicotinamide (4j): Yield: 57% (38.6 mg) as a yellow solid;
mp = 141.8ꢀ142.5 oC; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.63 (d,
J = 7.2 Hz, 1H), 7.49ꢀ7.45 (m, 2H), 7.44ꢀ7.39 (m, 2H), 6.24 (s, 1H), 2.95 (d, J = 4.0
Hz, 3H), 2.68 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 169.5, 157.6, 156.1,
138.7, 135.6, 129.9, 129.4, 128.8, 127.1, 117.3, 26.8, 23.3; IR (KBr): 3066, 2927,
1646, 1551, 1307, 1163, 839, 764, 696 cm−1; MS (EI) m/z 77, 105, 115, 141, 153, 168,
196, 211, 226; HRMSꢀESI (m/z): calcd for C14H15N2O, [M+H]+ : 227.1179, found,
227.1186.
N,N,2-Trimethyl-6-phenylnicotinamide (4k): Yield: 64% (46.1 mg) as a yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.6 Hz, 2H), 7.59ꢀ7.44 (m, 2H), 7.46 (t, J
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= 7.3 Hz, 2H), 7.42ꢀ7.38 (m, 1H), 3.15 (s, 3H), 2.89 (s, 3H), 2.58 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3) δ 170.1, 157.2, 154.3, 138.9, 134.9, 130.1, 129.2, 128.8,
127.0, 117.7, 38.5, 34.8, 22.5; IR (KBr): 3060, 2927, 1641, 1586, 1442, 1396, 1269,
1061, 753, 694 cm−1; MS (EI) m/z 77, 83, 115, 141, 153, 168, 196, 225, 240;
HRMSꢀESI (m/z): calcd for C15H17N2O, [M+H]+ : 241.1335, found, 241.1340.
2-Methyl-6-phenyl-3-tosylpyridine (4l): Yield: 67% (64.9 mg) as a brown solid; mp
= 128.6ꢀ129.9 oC; 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.0 Hz, 1H), 8.03 (d, J =
6.0 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.45 (s, 3H), 7.32 (d, J
= 7.6 Hz, 2H), 2.74 (s, 3H), 2.41 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 160.4,
157.4, 144.6, 138.1, 137.7, 134.3, 130.2, 129.9, 128.9, 127.9, 127.4, 126.8, 117.9,
23.9, 21.6; IR (KBr): 3062, 2925, 1565, 1440, 1310, 1151, 1038, 688, 550 cm−1; MS
(EI) m/z 65, 77, 91, 115, 139, 156, 167, 207, 243, 258, 323; HRMSꢀESI (m/z): calcd
for C19H18NO2S, [M+H]+ : 324.1053, found, 324.1056.
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1-(2-Methyl-6-(p-tolyl)pyridin-3-yl)ethan-1-one (5a): Yield: 78% (52.7 mg) as a
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yellow solid; mp = 75.8ꢀ76.7 C; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.0 Hz,
1H), 7.96 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 2.84
(s, 3H), 2.61 (s, 3H), 2.41 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 199.9, 158.6,
158.5, 140.0, 138.1, 135.5, 130.4, 129.6, 127.2, 117.0, 29.3, 25.3, 21.4; IR (KBr):
2921, 1680, 1579, 1261, 821 cm−1; MS (EI) m/z 65, 91, 115, 167, 182, 210, 225;
HRMSꢀESI (m/z): calcd for C15H16NO, [M+H]+ : 226.1226, found, 226.1235.
1-(6-(4-Methoxyphenyl)-2-methylpyridin-3-yl)ethan-1-one (5b): Yield: 77% (55.7
mg) as a yellow solid; mp = 109.4ꢀ110.8 oC; 1H NMR (400 MHz, CDCl3) δ 8.01 (dd,
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J = 10.8, 8.9 Hz, 3H), 7.55 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 3.85 (s, 1H),
2.82 (s, 1H), 2.58 (s, 1H); 13C {1H} NMR (100 MHz, CDCl3) δ 199.8, 161.2, 158.6,
158.2, 138.1, 130.8, 129.9, 128.7, 116.4, 114.2, 55.4, 29.2, 25.4; IR (KBr): 2968,
1684, 1606, 1576, 1510, 1434, 1259, 1026, 827 cm−1; MS (EI) m/z 63, 77, 108, 113,
128, 140, 154, 171, 183, 198, 226, 241; HRMSꢀESI (m/z): calcd for C15H16NO2,
[M+H]+ : 242.1176, found, 242.1181.
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1-(6-(4-Fuorophenyl)-2-methylpyridin-3-yl)ethan-1-one (5c): Yield: 80% (55.0 mg)
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as a yellow solid; mp = 71.3ꢀ72.5 C; H NMR (400 MHz, CDCl3) δ 8.07ꢀ8.04 (m,
3H), 7.60 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.4 Hz, 2H), 2.84 (s, 3H), 2.61 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3) δ 199.8, 164.0 (J = 248.4 Hz), 158.0, (J = 116.4 Hz),
138.2, 134.3, 130.7, 129.3 (J = 8.5 Hz), 127.8 (J = 8.1 Hz), 117.0, 115.8 (J = 21.6 Hz),
29.3, 25.2; IR (KBr): 2928, 1681, 1581, 1504, 1355, 1263, 1162, 823 cm−1; MS (EI)
m/z 63, 75, 92, 133, 159, 171, 186, 214, 229; HRMSꢀESI (m/z): calcd for C14H13FNO,
[M+H]+ : 230.0976, found, 230.0984.
1-(6-(4-Chlorophenyl)-2-methylpyridin-3-yl)ethan-1-one (5d) Yield: 65% (47.8 mg)
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as a yellow solid; mp = 91.5ꢀ92.8 C; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.0
Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H),
2.83 (s, 3H), 2.61 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 199.8, 158.7, 157.3,
138.1, 136.7, 136.0, 131.0, 129.0, 128.6, 117.1, 29.3, 25.2; IR (KBr): 2926, 1679,
1578, 1577, 1353, 817 cm−1; MS (EI) m/z 63, 75, 83, 115, 139, 167, 175, 202, 230,
245; HRMSꢀESI (m/z): calcd for C14H13ClNO, [M+H]+ : 246.0680, found, 246.0684.
1-(6-(4-Bromophenyl)-2-methylpyridin-3-yl)ethan-1-one (5e): Yield: 62% (53.8
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mg) as a yellow solid; mp = 98.0ꢀ99.3 oC; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J =
8.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.62 ꢀ7.59 (m, 3H), 2.83 (s, 3H), 2.61 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3) δ 199.8, 158.7, 157.3, 138.1, 137.1, 132.0, 131.0,
128.8, 124.4, 117.0, 29.3, 25.2; IR (KBr): 2925, 1677, 1578, 1430, 1260, 817, 761
cm−1; MS (EI) m/z 63, 115, 140, 167, 207, 274, 289; HRMSꢀESI (m/z): calcd for
C14H13BrNO, [M+H]+ : 290.0175, found, 290.0173.
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1-(6-(4-Iodophenyl)-2-methylpyridin-3-yl)ethan-1-one (5f): Yield: 76% (76.8 mg)
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as a yellow solid; mp = 123.1ꢀ124.3 C; H NMR (400 MHz, CDCl3) δ 8.04 (d, J =
8.0 Hz, 1H), 7.81 (s, 3H), 7.61 (d, J = 5.6 Hz, 2H), 2.83 (s, 3H), 2.61 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3) δ 199.9, 158.7, 157.5, 138.1, 138.0, 132.0, 129.0, 128.9,
117.0, 96.34, 29.4, 25.2; IR (KBr): 1676, 1575, 1431, 1260, 818 cm−1; MS (EI) m/z
76, 83, 115, 140, 161, 167, 294, 322, 337; HRMSꢀESI (m/z): calcd for C14H13INO,
[M+H]+ : 338.0036, found, 338.0031.
4-(5-Acetyl-6-methylpyridin-2-yl)benzonitrile (5g): Yield: 63% (44.6 mg) as a
yellow solid; mp = 169.9ꢀ170.7 ℃; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.0 Hz,
2H), 8.09 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 1H), 2.84
(s, 3H), 2.63 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 199.8, 158.8, 156.2, 142.3,
138.1, 132.6, 131.9, 127.8, 118.7, 117.9, 113.1, 29.4, 25.1; IR (KBr): 2924, 2851,
2224, 1678, 1574, 1427, 1353, 1261, 822 cm−1; MS (EI) m/z 63, 140, 166, 178, 193,
221, 236; HRMSꢀESI (m/z): calcd for C15H13N2O, [M+H]+ : 237.1022, found,
237.1021.
1-(2-Methyl-6-(4-nitrophenyl)pyridin-3-yl)ethan-1-one (5h): Yield: 79% (60.7 mg)
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as a yellow solid; mp = 140.1ꢀ141.2 C; 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J =
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13C {1H} NMR (100 MHz, CDCl3) δ 199.9, 158.8, 155.7, 148.5, 144.2, 138.1, 132.0,
128.1, 124.0, 118.2, 29.4, 25.1; IR (KBr): 2926, 1682, 1582, 1560, 1344, 1263, 826,
742 cm−1; MS (EI) m/z 70, 115, 140, 167, 196, 213, 241, 256; HRMSꢀESI (m/z):
calcd for C14H13N2O3, [M+H]+ : 257.0921, found, 257.0927.
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1-(5-Butyl-2-methyl-6-phenylpyridin-3-yl)ethan-1-one (5i): Yield: 52% (41.7 mg)
as a yellow oil;1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.88 (d, J =
7.6 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.21ꢀ7.17 (m, 2H), 2.75 (s, 3H), 2.58 (t, J = 7.7
Hz, 2H), 2.51 (s, 3H), 1.58ꢀ1.50 (m, 2H), 1.33ꢀ1.24 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H);
13C {1H} NMR (100 MHz, CDCl3) δ 199.9, 158.8, 158.6, 144.9, 138.0, 135.8, 130.3,
129.0, 127.2, 116.9, 35.5, 33.5, 29.3, 25.4, 22.3, 14.0; IR (KBr): 2961, 2928, 2858,
1686, 1580, 1262, 825 cm−1; MS (EI) m/z 89, 91, 115, 141, 153, 168, 181, 196, 209,
224, 238, 252, 267; HRMSꢀESI (m/z): calcd for C18H22NO, [M+H]+ : 268.1696,
found, 268.1704.
1-(2-Methyl-5,6-diphenylpyridin-3-yl)ethan-1-one (5j): Yield: 81% (69.7 mg) as a
yellow solid; mp = 87.9ꢀ89.1 oC; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.39 (d,
J = 6.0 Hz, 2H), 7.27 (s, 3H), 7.22 (d, J = 6.4 Hz, 3H), 7.19ꢀ7.17 (m, 2H), 2.86 (s, 3H),
2.62 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.0, 158.4, 156.8, 139.8, 139.3,
139.1, 133.3, 130.9, 130.0, 129.5, 128.6, 128.4, 128.0, 127.5, 29.4, 24.8; IR (KBr):
3058, 2926, 1690, 1579, 1530, 1424, 1250, 1214, 800, 766 cm−1; MS (EI) m/z 77, 91,
115, 121, 139, 166, 202, 215, 244, 287; HRMSꢀESI (m/z): calcd for C20H17NO,
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[M+H]+ : 288.1383, found, 288.1387.
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1-(2-Methyl-5,6-dihydrobenzo[h]quinolin-3-yl)ethan-1-one (5k): Yield: 67% (47.6
mg) as a yellow solid; mp = 106.3ꢀ107.8 oC; 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J
= 6.8 Hz, 1H), 7.77 (s, 1H), 7.40ꢀ7.28 (m, 2H), 7.21 (d, J = 7.2 Hz, 1H), 2.93 (s, 4H),
2.80 (s, 3H), 2.58 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.0, 156.6, 153.9,
138.7, 136.8, 133.8, 130.8, 129.9, 128.6, 127.9, 127.3, 125.6, 29.3, 28.0, 27.4, 25.1;
IR (KBr): 2928, 2843, 1683, 1589, 1581, 1436, 1350, 1251, 748 cm−1; MS (EI) m/z
96, 115, 152, 167, 178, 194, 222, 237; HRMSꢀESI (m/z): calcd for C16H16NO,
[M+H]+ : 238.1226, found, 238.1231.
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1-(6-(Furan-2-yl)-2-methylpyridin-3-yl)ethan-1-one (5l): Yield: 79% (47.6 mg) as
a red oil; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 6.0 Hz,
2H), 7.16 (d, J = 2.8 Hz, 1H), 6.54 (s, 1H), 2.78 (s, 3H), 2.57 (s, 3H); 13C {1H} NMR
(100 MHz, CDCl3) δ 199.4, 159.0, 153.1, 150.3, 144.3, 138.0, 130.2, 115.3, 112.4,
110.8, 29.2, 25.3; IR (KBr): 2926, 1686, 1597, 1262, 745 cm−1; MS (EI) m/z 63 77,
103, 130, 140, 158, 186, 201; HRMSꢀESI (m/z): calcd for C12H12NO2, [M+H]+ :
202.0863, found, 202.0869.
1-(2-Methyl-6-(thiophen-2-yl)pyridin-3-yl)ethan-1-one (5m): Yield: 81% (52.7 mg)
1
as a red oil; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 2.8
Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 4.8 Hz, 1H), 7.13ꢀ7.11 (m, 1H), 2.79 (s,
3H), 2.57 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 199.3, 159.0, 153.7, 144.0,
138.1, 130.2, 129.2, 128.3, 126.1, 115.5, 29.2, 25.3; IR (KBr): 2926, 1683, 1581,
1424, 1260, 1150, 823, 707 cm−1; MS (EI) m/z 63, 86, 130, 140, 147, 159, 174, 202,
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217; HRMSꢀESI (m/z): calcd for C12H12NOS, [M+H]+ : 218.0634, found, 218.0639.
1-(6-Methyl-[2,4'-bipyridin]-5-yl)ethan-1-one (5n): Yield: 87% (55.3 mg) as a
yellow solid; mp = 78.6ꢀ79.5 oC; 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 2H), 8.06 (d,
J = 8.0 Hz, 1H), 7.92 (d, J = 4.4 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 2.81 (s, 3H), 2.59
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 199.9, 158.8, 155.6, 150.4, 145.4, 138.0,
132.4, 121.3, 117.8, 29.4, 25.1; IR (KBr): 2926, 1688, 1560, 1415, 1262, 958, 820,
686 cm−1; MS (EI) m/z 78, 98, 115, 142, 169, 197, 212; HRMSꢀESI (m/z): calcd for
C13H13N2O, [M+H]+ : 213.1022, found, 213.1027.
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1-(6-Methyl-[2,2'-bipyridin]-5-yl)ethan-1-one (5o): Yield: 59% (37.5 mg) as a
o
brown solid; mp = 77.1ꢀ78.4 C; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.49 (d,
J = 7.6 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.0 Hz,
1H), 7.33 (s, 1H), 2.83 (s, 3H), 2.62 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ
200.2, 158.0, 157.2, 155.2, 149.3, 138.0, 137.0, 132.2, 124.3, 121.8, 118.0, 29.4, 25.2;
IR (KBr): 2925, 2856, 1683, 1580, 1551, 1432, 1356, 1253, 794, 747 cm−1; MS (EI)
m/z 78, 117, 142, 169, 197, 212; HRMSꢀESI (m/z): calcd for C13H13N2O, [M+H]+ :
213.1022, found, 213.1026.
1-(2,6-Dimethylpyridin-3-yl)ethan-1-one (5p): Yield: 54% (24.1 mg) as a yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 2.73
(s, 3H), 2.56 (s, 6H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.0, 160.8, 158.0, 137.4,
130.0, 120.3, 29.2, 24.8, 24.6; IR (KBr): 2924, 2856, 1679, 1582, 1437, 1366, 1226,
1053 cm−1; MS (EI) m/z 77, 79, 106, 134, 149 ; HRMSꢀESI (m/z): calcd for C9H12NO,
[M+H]+ : 150.0913, found, 150.0916.
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1-(5-Butyl-2-methyl-6-propylpyridin-3-yl)ethan-1-one (5q): Yield: 62% (43.3 mg)
as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 2.79ꢀ2.75 (m, 2H), 2.68 (s,
3H), 2.61ꢀ2.57 (m, 2H), 2.55 (s, 3H), 1.69ꢀ1.56 (m, 4H), 1.46ꢀ1.375 (m, 2H), 0.99 (t,
J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.4,
162.9, 154.9, 137.8, 132.1, 130.3, 34.9, 33.8, 31.9, 29.3, 24.4, 23.9, 22.9, 14.0; IR
(KBr): 2962, 2927, 2867, 1687, 1544, 1439, 1263, 940 cm−1; MS (EI) m/z 77, 91, 163,
176, 191, 204, 218, 233; HRMSꢀESI (m/z): calcd for C15H24NO, [M+H]+ : 234.1852,
found, 234.1858.
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1-(6-Benzyl-2-methyl-5-phenylpyridin-3-yl)ethan-1-one (5r): Yield: 78% (70.4 mg)
as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.41 (s, 3H), 7.21 (d, J =
4.4 Hz, 2H), 7.18ꢀ7.11 (m, 3H), 7.01 (d, J = 7.2 Hz, 2H), 4.15 (s, 2H), 2.83 (s, 3H),
2.58 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.1, 159.9, 156.9, 139.3, 138.8,
134.6, 130.4, 129.3, 128.8, 128.5, 128.2, 127.7, 126.1, 41.7, 29.3, 24.7; IR (KBr):
3060, 3027, 2925, 2851, 1687, 1586, 1534, 1429, 1224, 700 cm−1; MS (EI) m/z 73, 91,
207, 224, 281, 301; HRMSꢀESI (m/z): calcd for C21H19NNaO, [M+Na]+ : 324.1359,
found, 324.1363.
1-(6-Cyclopropyl-2-methylpyridin-3-yl)ethan-1-one (5s): Yield: 47% (24.7 mg) as
a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0
Hz, 1H), 2.68 (s, 3H), 2.54 (s, 3H), 2.07ꢀ2.01 (m, 1H), 1.06 (s, 2H), 1.02 (d, J = 8.4
Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3) δ 199.8, 165.5, 158.4, 137.1, 129.3,
117.7, 29.1, 25.2, 17.5, 10.6; IR (KBr): 2925, 2853, 1684, 1586, 1264, 1144, 960, 818
cm−1; MS (EI) m/z 65 77, 117, 132, 160, 175; HRMSꢀESI (m/z): calcd for C11H14NO,
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[M+H]+ : 176.1070, found, 176.1074.
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1-(2-Methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)ethan-1-one (5t): Yield:
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62% (32.6 mg) as a red oil; H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 3.02 (t, J =
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7.6 Hz, 2H), 2.95 (t, J = 7.4 Hz, 2H), 2.71 (s, 3H), 2.56 (s, 3H), 2.19ꢀ2.12 (m, 2H);
13C {1H} NMR (100 MHz, CDCl3) δ 200.6, 167.9, 156.4, 134.4, 133.0, 130.8, 34.4,
30.2, 29.5, 24.4, 23.1; IR (KBr): 2962, 2925, 1601, 1553, 1429, 1357, 1267, 740 cm−1;
MS (EI) m/z 65, 77, 91, 111, 132, 160, 175; HRMSꢀESI (m/z): calcd for C11H14NO,
[M+H]+ : 176.1070, found, 176.1075.
1-(2-Methyl-5,6,7,8-tetrahydroquinolin-3-yl)ethan-1-one (5u): Yield: 69% (39.1
mg) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 2.90 (t, J = 6.2 Hz,
2H), 2.76 (t, J = 5.9 Hz, 2H), 2.68 (s, 3H), 2.54 (s, 3H), 1.88 (d, J = 5.6 Hz, 2H), 1.81
(d, J = 5.6 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.2, 159.8, 155.0, 138.0,
130.3, 129.4, 32.5, 29.2, 28.3, 24.3, 22.8, 22.6; IR (KBr): 2931, 1684, 1549, 1440,
1149, 930 cm−1; MS (EI) m/z 77, 91, 119, 131, 146, 174, 189; HRMSꢀESI (m/z):
calcd for C12H16NO, [M+H]+ : 190.1226, found, 190.1232.
1-(2-Methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl)ethan-1-one (5v):
o
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Yield: 81% (49.3 mg) as a yellow solid; mp = 67.3ꢀ68.6 C; H NMR (400 MHz,
CDCl3) δ 7.65 (s, 1H), 3.02 (d, J = 7.6 Hz, 2H), 2.77 (d, J = 7.2 Hz, 2H), 2.67 (s, 3H),
2.54 (s, 3H), 1.86 (s, 2H), 1.67 (s, 4H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.3,
165.6, 154.7, 137.6, 135.1, 130.3, 39.4, 34.8, 32.7, 29.3, 27.9, 26.3, 24.3; IR (KBr):
2924, 2851, 1685, 1590, 1549, 1436, 1283, 1254, 944 cm−1; MS (EI) m/z 77, 91, 118,
133, 160, 188, 203; HRMSꢀESI (m/z): calcd for C13H18NO, [M+H]+ : 204.1383,
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found, 204.1391.
1-(2-Methyl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-3-yl)ethan-1-one
(5w):
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Yield: 82% (53.4 mg) as a yellow solid; mp = 51.2ꢀ52.6 C; H NMR (400 MHz,
CDCl3) δ 7.64 (s, 1H), 2.96ꢀ2.93 (m, 2H), 2.78ꢀ2.75 (m, 2H), 2.68 (s, 3H), 2.55 (s,
3H), 1.78 (s, 2H), 1.69 (s, 2H), 1.37 (s, 4H); 13C {1H} NMR (100 MHz, CDCl3) δ
200.4, 163.6, 155.4, 137.5, 133.2, 130.8, 34.7, 32.1, 31.5, 30.5, 29.3, 25.9, 25.8, 24.4;
IR (KBr): 2925, 2853, 1688, 1591, 1548, 1436, 1356, 1264, 941, 648 cm−1; MS (EI)
m/z 77, 91, 117, 146, 174, 188, 202, 217; HRMSꢀESI (m/z): calcd for C14H20NO,
[M+H]+ : 218.1539, found, 218.1542.
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(S)-1-(2,8-Dimethyl-5-(prop-1-en-2-yl)-5,6-dihydroquinolin-3-yl)ethan-1-one (5x):
Yield: 44% (31.8 mg) as a red oil; 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 6.17 (s,
1H), 4.95 (s, 1H), 4.80ꢀ4.75 (m, 1H), 3.61 (t, J = 8.7 Hz, 1H), 2.73 (s, 3H), 2.54 (s,
3H), 2.44 (d, J = 6.0 Hz, 2H), 2.14 (s, 3H), 1.73 (s, 3H); 13C {1H} NMR (100 MHz,
CDCl3) δ 200.2, 155.8, 155.7, 145.5, 135.4, 134.5, 130.5, 130.3, 129.4, 114.3, 45.2,
29.3, 27.7, 24.8, 19.7, 18.0; IR (KBr): 3077, 2973,2924, 1686, 1586, 1437, 1357,
1265, 1230, 899, 830 cm−1; MS (EI) m/z 65, 77, 91, 115, 128, 142, 158, 184, 200, 213,
236, 241; HRMSꢀESI (m/z): calcd for C16H20NO, [M+H]+ : 242.1539, found,
242.1544.
(E)-1-(2-Methyl-6-(2-(2,6,6-trimethylcyclohex-1-en-1-yl)vinyl)pyridin-3-yl)ethan-
1-one (5y): Yield: 47% (39.9 mg) as a red oil; 1H NMR (400 MHz, CDCl3) δ 7.93 (d,
J = 8.0 Hz, 1H), 7.36 (d, J = 16.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 16.0
Hz, 1H), 2.77 (s, 3H), 2.57 (s, 3H), 2.07 (t, J = 5.8 Hz, 2H), 1.81 (s, 3H), 1.63 (d, J =
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5.6 Hz, 2H), 1.50 (d, J = 5.6 Hz, 2H), 1.10 (s, 6H); 13C {1H} NMR (100 MHz, CDCl3)
δ 199.6, 158.6, 157.9, 137.7, 137.1, 134.8, 132.3, 131.4, 130.0, 117.8, 39.8, 34.3, 33.3,
29.2, 29.0, 25.4, 21.9, 19.1; IR (KBr): 2966, 2927, 2854, 1687, 1578, 1461, 1256, 970,
676 cm−1; MS (EI) m/z 77, 91, 119, 149, 207, 260, 268, 283; HRMSꢀESI (m/z): calcd
for C19H26NO, [M+H]+ : 284.2009, found, 284.2009.
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1-(2-Methyl-4,6-diphenylpyridin-3-yl)ethan-1-one (7a): Yield: 63% (54.2 mg) as a
yellow solid; mp = 102.4ꢀ103.9 oC; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.2 Hz,
2H), 7.58 (s, 1H), 7.50ꢀ7.44 (m, 6H), 7.43 (s, 2H), 2.64 (s, 3H), 2.02 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3) δ 206.3, 157.0, 154.1, 147.3, 138.8, 138.4, 134.5, 129.3,
129.1, 129.0, 128.8, 128.5, 127.2, 118.6, 32.1, 23.0; IR (KBr): 3061, 2925, 1696,
1578, 1539, 753, 670 cm−1; MS (EI) m/z 77, 115, 143, 203, 244, 272, 287;
HRMSꢀESI (m/z): calcd for C20H18NO, [M+H]+ : 288.1383, found, 288.1385.
1-(4-(4-Methoxyphenyl)-2-methyl-6-phenylpyridin-3-yl)ethan-1-one (7b): Yield:
o
38% (36.1 mg) as a yellow solid; mp = 99.6ꢀ100.7 C; 1H NMR (400 MHz, CDCl3) δ
8.03 (d, J = 7.2 Hz, 2H), 7.55 (s, 1H), 7.47 (t, J = 6.9 Hz, 2H), 7.43 (d, J = 6.8 Hz,
1H), 7.35 (d, J = 7.2 Hz, 2H), 6.99 (d, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.62 (s, 3H), 2.03
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 206.7, 160.3, 157.0, 154.0, 147.0, 138.9,
134.4, 130.6, 129.8, 129.3, 128.8, 127.2, 118.5, 114.5, 55.4, 32.0, 23.0; IR (KBr):,
2930, 2838, 1695, 1608, 1576, 1512, 1252, 1180, 1030, 837, 764, 694 cm−1; MS (EI)
m/z 77, 115, 189, 233, 302, 317; HRMSꢀESI (m/z): calcd for C21H20NO2, [M+H]+ :
318.1489, found, 318.1494.
1-(4-(4-Fluorophenyl)-2-methyl-6-phenylpyridin-3-yl)ethan-1-one (7c): Yield:
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61% (55.8 mg) as a yellow solid; mp = 135.7ꢀ136.3 C; 1H NMR (400 MHz, CDCl3)
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δ 8.03 (d, J = 7.2 Hz, 2H), 7.53 (s, 1H), 7.48ꢀ7.43 (m, 3H), 7.41ꢀ7.39 (m, 2H), 7.17 (t,
J = 8.3 Hz, 2H), 2.62 (s, 3H), 2.04 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ
206.1, 163.3 (J = 248.0 Hz), 157.1, 154.1, 146.1, 138.6, 134.5, 134.3 (J = 3.3 Hz),
130.4 (J = 8.3 Hz), 129.4, 128.8, 127.1, 118.5, 116.1 (J = 21.5 Hz), 32.11, 23.00; IR
(KBr): 3059, 2925, 2856, 1695, 1585, 1507, 1357, 842, 765, 693 cm−1; MS (EI) m/z
77, 110, 152, 221, 290, 305; HRMSꢀESI (m/z): calcd for C20H17FNO, [M+H]+ :
306.1289, found, 306.1291.
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1-(4-(4-Chlorophenyl)-2-methyl-6-phenylpyridin-3-yl)ethan-1-one (7d): Yield:
64% (61.3 mg) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.2 Hz, 2H),
7.53 (s, 1H), 7.49 (d, J = 6.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 3H), 7.35 (d, J = 7.6 Hz,
2H), 2.62 (s, 3H), 2.05 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 206.0, 157.2,
154.2, 145.9, 138.6, 136.7, 135.4, 134.4, 129.9, 129.5, 129.3, 128.8, 127.1, 118.3,
32.2, 23.1; IR (KBr): 2925, 1697, 1595, 1491, 1353, 1252, 1090, 834, 694 cm−1; MS
(EI) m/z 77, 143, 202, 237, 306, 321; HRMSꢀESI (m/z): calcd for C20H17ClNO,
[M+H]+ : 322.0993, found, 322.0998.
1-(4-(4-Bromophenyl)-2-methyl-6-phenylpyridin-3-yl)ethan-1-one (7e): Yield:
o
73% (79.9 mg) as a yellow solid; mp = 104.6ꢀ105.7 C; 1H NMR (400 MHz, CDCl3)
δ 8.02 (d, J = 6.8 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.52 (s, 1H), 7.49ꢀ7.43 (m, 3H),
7.28 (d, J = 7.7 Hz, 2H), 2.62 (s, 3H), 2.05 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3)
δ 205.9, 157.2, 154.2, 145.9, 138.6, 137.2, 134.3, 132.3, 130.1, 129.5, 128.8, 127.1,
123.6, 118.2, 32.2, 23.0; IR (KBr): 2924, 1697, 1586, 1536, 1488, 1353, 1254, 831,
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694 cm−1; MS (EI) m/z 77, 120, 142, 202, 271, 350, 365; HRMSꢀESI (m/z): calcd for
C20H17BrNO, [M+H]+ : 366.0488, found, 366.0492.
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4-(3-Acetyl-2-methyl-6-phenylpyridin-4-yl)benzonitrile (7f): Yield: 79% (73.9 mg)
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as a yellow solid; mp = 150.4ꢀ152.1 C; H NMR (400 MHz, CDCl3) δ 8.02 (d, J =
7.2 Hz, 2H), 7.75 (d, J = 7.6 Hz, 2H), 7.52 (d, J = 7.2 Hz, 3H), 7.49ꢀ7.43 (m, 3H),
2.62 (s, 3H), 2.06 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 205.4, 157.4, 154.4,
145.1, 142.9, 138.3, 134.2, 132.7, 129.7, 129.3, 128.9, 127.1, 118.2, 118.0, 113.0,
32.4, 23.1; IR (KBr): 3062, 2925, 2853, 2229, 1697, 1580, 1536, 1354, 1254, 844,
785, 695 cm−1; MS (EI) m/z 77, 207, 228, 297, 312; HRMSꢀESI (m/z): calcd for
C21H17N2O, [M+H]+ : 313.1335, found, 313.1341.
1-(2-Methyl-4-(4-nitrophenyl)-6-phenylpyridin-3-yl)ethan-1-one (7g): Yield: 77%
(76.7 mg) as a yellow solid; mp = 130.3ꢀ131.9 oC; 1H NMR (400 MHz, CDCl3) δ 8.32
(d, J = 7.6 Hz, 2H), 8.04 (d, J = 6.4 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H),
7.51ꢀ7.44 (m, 3H), 2.64 (s, 3H), 2.09 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ
205.3, 157.4, 154.4, 148.2, 144.8, 138.3, 134.2, 129.7, 129.6, 128.9, 128.8, 127.1,
124.1, 118.0, 32.4, 23.1; IR (KBr): 3066, 2925, 2855, 1698, 1601, 1520, 1349, 1233,
857, 696 cm−1; MS (EI) m/z 77, 139, 202, 248, 271, 317, 332; HRMSꢀESI (m/z):
calcd for C20H17N2O3, [M+H]+ : 333.1234, found, 333.1238.
4-(3-Acetyl-2-methyl-6-phenylpyridin-4-yl)benzaldehyde (7h): Yield: 44% (41.6
mg) as a yellow solid; mp = 152.2ꢀ153.7 oC; 1H NMR (400 MHz, CDCl3) δ 10.10 (s,
1H), 8.04 (d, J = 7.2 Hz, 2H), 7.99 (d, J = 7.6 Hz, 2H), 7.61 (s, 1H), 7.58 (d, J = 7.2
Hz, 2H), 7.51ꢀ7.45 (m, 3H), 2.65 (s, 3H), 2.06 (s, 3H); 13C {1H} NMR (100 MHz,
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