Domino reactions involving the branched C-N and C=C cleavage of enaminones toward pyridines synthesis

Article abstract of DOI:10.1021/jo5018266

The copper-catalyzed cascade reactions of enaminones and ammonium chloride have led to the unprecedented synthesis of 4-unsubstituted pyridines of both symmetrical and unsymmetrical structures. Under the aerobic copper-catalyzed conditions, the branched t

Full text of DOI:10.1021/jo5018266

Note
pubs.acs.org/joc
Domino Reactions Involving the Branched C−N and CC Cleavage
of Enaminones Toward Pyridines Synthesis
Jie-Ping Wan,* Youyi Zhou, and Shuo Cao
Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P. R. China
*
S Supporting Information
ABSTRACT: The copper-catalyzed cascade reactions of
enaminones and ammonium chloride have led to the
unprecedented synthesis of 4-unsubstituted pyridines of both
symmetrical and unsymmetrical structures. Under the aerobic
copper-catalyzed conditions, the branched transformations of
enaminones with C−N and CC bond cleavage provide the
C2-C3/C5-C6 and C4 building blocks to construct the
pyridine ring, respectively. The CC cleavage that provides
the C4 atom in the pyridine product is the first example
showing the reactivity of an enaminone as the donor of one carbon synthon.
1
2
he enaminones that contain the OC-CC-NR R
heterocycle. Particularly, in recent years, the pyridine synthesis
has received dramatic progress as promoted by the rapid
occurrence of many novel synthetic tools and concepts.
T
backbone have been known as highly reactive and
versatile building blocks in organic synthesis. Their applica-
tions have been found in the synthesis of numerous organic
products of different central backbones, such as heterocycles,
benzene aromatics, acyclic molecules, and natural products.
According to the available literature on the enaminone-based
synthesis, the major reactive sites in enaminones consist of the
electrophilic carbon in the carbonyl, the nucleophilic α-carbon
1
11
Among the important strategies for pyridine synthesis,
exploring new C4 sources to construct pyridine ring constitutes
a critical issue. As a typical example, Guan and co-workers have
recently reported the pyridine synthesis using DMF as C4
resource, which leads to the synthesis of a class of useful
symmetrical pyridines 2 using ketoxime acetates 1 (eq 1,
2
3
4
5
1
2
12
and amino group, (R and/or R = H) as well as the easily
Scheme 1). Herein, we report a new tactic for pyridine
1
2
1
cleavable active C−N bond (R , R ≠ H). Interestingly, as a
central fragment in the molecule, the CC bond has scarcely
been found to undergo a transformation in enaminone-based
organic synthesis. While the CC bond is a fundamental
organic functional group possessing tremendous reactivity, the
highly polar CC bond in enaminones, as activated by both
the electron-donating amino group and the electron-with-
drawing carbonyl group, is reasonably of high potential to act as
the reactive fragment in enaminone-based reactions. In this
context, exploring new reaction pathways by functionalizing the
CC bond is presently an issue of significance in order to
expand the frontiers of enaminone chemistry.
synthesis by employing the assembly of enaminones 3 and
ammonium chloride wherein enaminones undergo the
branched C−N and CC bond cleavage to, respectively,
provide the C2-C3/C5-C6 and C4 fragments to construct the
pyridines 4 (eq 2, Scheme 1). Among the domino trans-
formations, the CC bond cleavage that provides C4 carbon
Scheme 1. Synthesis of Pyridines with Novel C4 Sources
A pyridine ring is a fundamental heterocyclic motif showing
up in numerous natural products, therapeutic agents, and
6
materials. In addition, as an electron-deficient aromatic system,
7
pyridines have also been well-known as useful organic bases,
8
ligands, as well as central building blocks in a broad array of
organic syntheses. Therefore, it is not surprising that the
9
research interest toward the synthesis of pyridines remains
highly active and extensive in despite of the long history of
pyridine chemistry. Since the discovery of the classical
Hantzsch pyridine synthesis by oxidizing 1,4-dihydropyr-
1
0
idines, spectacular advances have been achieved in the area
of pyridine synthesis, as demonstrated by the reports of
numerous alternative synthetic methodologies targeting on this
Received: August 7, 2014
Published: September 18, 2014
©
2014 American Chemical Society
9872
dx.doi.org/10.1021/jo5018266 | J. Org. Chem. 2014, 79, 9872−9877

The Journal of Organic Chemistry
Note
represents a particularly interesting reaction pathway of
enaminones. To the best of our knowledge, this is the first
time that an enaminone has been found to be capable of
donating a single carbon in enaminone-based organic synthesis.
Initially, the titled transformation was observed by subjecting
enaminone 3a with ammonium chloride in the presence of
CuBr. Therefore, the reaction between 3a and ammonium
chloride providing pyridine 4a was systematically investigated
to optimize the reaction conditions. First, a class of different
Cu(I) and Cu(II) catalysts were employed, respectively. The
entries using different copper catalysts, including CuBr, CuCl,
were included in Table 2. According to the acquired data, the
present protocol was generally applicable for the synthesis of
Table 2. Synthesis of Different Symmetrical Pyridines
a
entry
Ar
product
yield (%)
1
2
3
4
5
6
7
8
9
Ph
4a
4b
4c
4d
4e
4f
85
83
72
56
77
93
87
62
77
84
65
74
62
68
94
86
91
58
CuI, Cu O, Cu(OAc) , CuO, CuBr , and CuCl , implied that
2
2
2
2
4-MeC H4
6
CuI was the best catalyst by providing 4a with 85% yield
4-MeOC H4
6
(
entries 1−8, Table 1). Subsequently, the variation on the
4-Me NC H
4
2
6
napth-1-yl
a
Table 1. Optimization of Reaction Conditions
4-ClC H4
6
4-ClC H4
4g
4h
4i
6
4-NCC H4
6
4-CF C H
4
3
6
1
1
1
1
1
1
0
1
2
3
4
5
4-NO C H
4
4j
2
6
2-MeC H4
4k
4l
6
3-MeOC H4
b
6
entry
catalyst
CuBr
solvent
T (°C)
yield (%)
3,4-(MeO) C H
3
4m
4n
4o
4p
4q
4r
2
6
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
120
120
120
120
120
120
120
120
120
120
110
130
120
120
120
120
120
120
120
81
79
67
69
80
75
78
85
78
84
74
81
trace
17
24
trace
nr
2-BrC H4
6
CuCl
3,4-Cl C H
3
2
6
Cu O
2
16
17
3-NO C H
2 6 4
Cu(OAc)2
thiophene-2-yl
napth-2-yl
CuO
1
8
CuBr2
CuCl2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
a
Yield of isolated product based on 0.2 mmol of enaminone 3.
c
9
d
symmetrical pyridines using aryl functionalized enaminones 3
via their branched transformations. In these entries using
enaminones containing a variety of different functional groups,
such as alkyl, alkoxyl, halide, nitro, amino, cyano, as well as
heteroaryl, the corresponding pyridines were provided with
good to excellent yields. Among these entries, the halogenated
aryl-based substrates gave excellent yields of related pyridines
10
11
12
13
14
15
16
17
18
19
EL
e
e
e
e
f
toluene
EtOH
(
4f, 4g, and 4o, Table 2). However, with the results afforded by
CH CN
3
the entries using other enaminones of either electron-deficient
or enriched structures, the electronic property showed no
deducible impact on the reaction results. Another notable point
in the results was the synthesis of thiophene-functionalized
pyridine 4q, which proved the good tolerance of the present
method to heteroaryl functionalized enaminones. However,
when the Ar fragment in enaminones 3 was alternated with an
alkyl such as methyl, the target transformation was not
observed under the standard conditions. In assigning the
product structure, the X-ray single crystal analysis on 4b was
conducted to provide confirmation of pyridine products on the
dioxane
DMSO
nr
59
a
Unless otherwise specified, the reaction conditions are 3a (0.6
mmol), NH Cl (0.3 mmol), copper catalyst (0.06 mmol) in 2 mL of
4
b
solvent(s), stirred for 12 h. Yield of isolated products based on 0.2
mmol of 3a. The CuI was 0.03 mmol. The CuI was 0.08 mol. The
reactions were run at reflux. NH OAc was employed as an alternative
c
d
e
f
4
ammonium source.
loading of CuI showed that 30 mol % was the most appropriate
loading (entries 9 and 10, Table 1). In addition, the reaction
under both higher and lower temperature did not display
improvement in the product yield, either (entries 11 and 12,
Table 1). Finally, a class of organic solvents of different polarity,
such as DMF, ethyl lactate (EL), toluene, etc., were also
subjected, and DMSO turned out to be among the best
mediums (entries 13−18, Table 1). Finally, the comparison
13
basis of other related spectroscopic analysis.
After the synthesis of symmetrical pyridines 4, we envisioned
that this synthetic method might also be expanded to the
synthesis of unsymmetrical pyridines by employing simulta-
neously two different enaminones. With the tentative attempt,
we found that the synthesis of unsymmetrical pyridines was
feasible, although related symmetrical pyridines were also
isolated as side products. To examine the scope, we then
performed expanded experiments of the type by combining
enaminones of different properties as substrates. As outlined in
Table 3, the entries could generally provide expected
unsymmetrical pyridines 5; however, together with the
symmetrical pyridines 4 which were resulted from the homo
experiments using different ammonium salts such as NH OAc
4
provided a lower yield of product than the entry using NH Cl
4
(
entry 19, Table 1).
On the basis of the optimized results, the syntheses of
different symmetrical pyridines 4 using different enaminone
substrates were then conducted. The results from this section
9
873
dx.doi.org/10.1021/jo5018266 | J. Org. Chem. 2014, 79, 9872−9877

The Journal of Organic Chemistry
Note
Table 3. Synthesis of Unsymmetrical Pyridines
With the acquired data as well as related literature, we
tentatively summarized the mechanism of the reaction. As
displayed in Scheme 3, the Cu(I) salt could activate the
Scheme 3. Plausible Mechanism for the Enaminone
Branched Synthesis of Pyridines
Ar1
Ar2
product
yield (%)
a
entry
1
2
3
4
5
6
7
8
9
Ph
4-MeOC H
5a/4a/4c
5b/4b/4c
5c/4b/4j
5d/4b/4q
5e/4i/4j
33/26/21
36/29/25
38/31/21
34/36/20
32/20/28
36/25/24
45/19/28
40/27/23
41/18/24
6
4
4
4-MeC H4
4-MeOC H
6
6
4-MeC H4
4-NO C H
4
6
2
6
4-MeC H4
thiophene-2-yl
4-NO C H
6
4-CF C H
3
6
4
4
2
6
4
4-CF C H
4-NCC H
4
5f/4i/4h
5g/4k/4p
5h/4l/4p
5i/4o/4m
3
6
6
2-MeC H4
3-NO C H
2 6
6
4
3-MeOC H
3-NO C H
2 6
6
4
4
3,4-Cl C H
3,4-(MeO) C H
2 6 4
2
6
4
a
Yield of isolated product based on 0.2 mmol of 3 (the 2 different
enaminones are used in 0.3 mmol + 0.3 mmol; it is assumed that
totally 0.2 mmol of enaminone(s) acted as C4 source).
assemblies of both enaminone substrates. In most of these
entries, the unsymmetrical pyridines 5 were provided with fair
yields that were higher than those of both symmetrical
byproducts 4; an exception was 5d, which was assembled
from the combination of aryl and heteroaryl functionalized
enaminones, was isolated with a slightly inferior yield over one
of the symmetrical pyridine product 4b. The results obtained
from these experiments, albeit with relatively lower yields,
demonstrated the applicability of the present method for the
synthesis of unsymmetrical pyridines.
In order to confirm the branched reaction pathway of
enaminones in the present synthesis, we designed control
experiments to explore the resource of C4 in pyridine products.
As shown in Scheme 2, when N,N-diethyl functionalized
enaminone to transition state 9, which could form peroxide
1
4
intermediates 10 as described in the literaure. The
nucleophilic attack of another enaminone to the peroxide
ring led to the production of intermediates 11, and the
automatic cleavage of 11 then led to the production of both
intermediates 12 and 13. The intermediates 12, upon
dehydration, provided iminium ion 14. The subsequent
nucleophilic addition of an additional enaminone molecule to
14 produced intermediates 15, which incorporated ammonium
1
5
to cyclize via double transamination to give 16. Finally, the
resulting intermediates 16 underwent aromatization to give
pyridine products by eliminating dimethylamine.
In conclusion, by employing copper catalysis, we have achieved
the synthesis of symmetrical and unsymmetrical pyridines via
the simple assemblies of enaminones and ammonium chloride.
The main factor that enables the construction of the pyridine
ring is the novel branched transformation of enaminones by
cleaving both C−N and CC bonds in this single reaction.
The CC bond cleavage is among the highly interesting since
the production of reactive intermediates resulted from this
transformation is not only important in the present synthesis
but also expected to be useful for the rational design of more
novel enaminone-based organic synthesis. Further research in
the field is presently ongoing in our group.
Scheme 2. Control Experiments in Confirming the C4
Source in the Pyridine Products
enaminone 6 was employed as the alternative starting material
EXPERIMENTAL SECTION
■
with NH Cl, the pyridine product 4a was obtained as the only
General Procedure for the Synthesis of Pyridines 4 and 5. In
a 25 mL round-bottom flask equipped with a stirring bar were located
enaminone(s) 3 (0.6 mmol) or (0.3 + 0.3 mmol, for the synthesis of
unsymmetrical pyridines), ammonium chloride (0.3 mmol), CuI (0.06
mmol), and DMSO (2 mL). The vessel was then stirred at 120 °C for
4
product, demonstrating that the C4 in the product was not
provided by the carbon in the N-alkyl fragment (eq 1, Scheme
2). In addition, when the enaminone 3c was subjected with o-
aminothiophenol 7 to the standard reaction condition, the 2-(p-
methoxylbenzoyl)benzothiazole 8 could be isolated with 18%
yield together with other unknown messy products (eq 2,
Scheme 1). This result clearly proved that the CC bond
could be cleaved under the present catalytic conditions and also
supported the fact that the C4 fragment in the pyridine was
donated by the β-carbon in the enaminone, as shown in eq 1.
1
2 h at an air atmosphere. After completion of the reaction (TCL), the
mixture was mixed with water (5 mL) and then extracted with ethyl
acetate (3 × 10 mL). The combined organic phase was dried over
anhydrous Na SO . After filtration, the organic solvent was removed
2
4
from the solution under reduced pressure. The resulting residue was
then subjected to silicon chromatography to give pure product by
using mixed ethyl acetate/petroleum ether as eluent (v/v = 1/10).
9
874
dx.doi.org/10.1021/jo5018266 | J. Org. Chem. 2014, 79, 9872−9877

The Journal of Organic Chemistry
Note
3
,5-Dibenzoylpyridine (4a). Yield: 49 mg; 85%; white solid; mp
2 H), 2.42 (s, 6 H); 13C NMR (100 MHz, CDCl ): δ 195.9, 154.3,
3
1
1
25−128 °C; H NMR (400 MHz, CDCl ): δ 9.18 (s, 2 H), 8.48 (s, 1
137.9, 137.8, 136.6, 133.3, 131.7, 131.5, 129.2, 125.6, 20.3; IR (KBr,
3
−
1
H), 7.85 (d, J = 8.0 Hz, 4 H), 7.67 (t, J = 7.2 Hz, 2 H), 7.55 (t, J = 7.6
cm ): 3050, 2955, 1665, 1550, 810; ESI-HRMS: Calcd for
Hz, 4 H); 13C NMR (100 MHz, CDCl ): δ 193.9, 153.2, 138.1, 136.2,
+
3
C H NO [M + H] 316.1338, found: 316.1354.
21 18
2
−1
1
7
2
33.6, 133.0, 130.0, 128.8; IR (KBr, cm ): 3065, 1660, 1550, 810,
40; ESI-HRMS: Calcd for C H NO [M + H] 288.1025, found:
3,5-Di(3-methoxyphenoyl) Pyridine (4l). Yield: 51 mg; 74%; pale
+
1
19
14
2
yellow solid; mp 70−72 °C; H NMR (400 MHz, CDCl ): δ 9.18 (s, 2
3
88.1035.
,5-Ditoloylpyridine (4b). Yield: 52 mg; 83%; gray solid; mp 140−
H), 8.48 (s, 1 H), 7.45−7.39 (m, 4 H), 7.35 (d, J = 7.6 Hz, 2 H), 7.20
(dd, J = 8.0 Hz, J = 2.0 Hz, 2 H), 3.88 (s, 6 H); C NMR (100
13
3
1 2
1
1
7
43 °C; H NMR (400 MHz, CDCl ): δ 9.16 (s, 2 H), 8.45 (s, 1 H),
MHz, CDCl ): δ 193.7, 160.0, 153.2, 138.1, 137.5, 133.0, 129.7, 122.8,
3
3
13
−1
.76 (d, J = 7.6 Hz, 4 H), 7.34 (d, J = 7.6 Hz, 4 H), 2.48 (s, 6 H);
NMR (100 MHz, CDCl ): δ 193.1, 152.4, 144.1, 137.4, 133.2, 132.8,
29.8, 129.0, 21.2; IR (KBr, cm ): 3050, 2900, 1665, 1535, 815; ESI-
HRMS: Calcd for C H NO [M + H] , 316.1338, found: 316.1346.
C
120.0, 114.2, 55.5; IR (KBr, cm ): 3065, 2870, 1665, 1480, 800; ESI-
HRMS: Calcd for C H NO [M + H] 348.1236, found: 348.1225.
+
3
21 18
4
−1
1
3
,5-Di(3,4-dimethoxyphenoyl) Pyridine (4m). Yield: 50 mg; 62%;
+
1
21
18
2
pink solid; mp 182−184 °C; H NMR (400 MHz, CDCl ): δ 9.12 (s,
H), 8.41 (s, 1 H), 7.53 (s, 2 H), 7.38 (d, J = 8.4 Hz, 2 H), 6.93 (d, J
= 8.4, 2 H), 3.98 (s, 6 H), 3.97 (s, 6 H); C NMR (100 MHz,
3
3
,5-Di(4-methoxyphenoyl) Pyridine (4c). Yield: 50 mg; 72%;
2
1
13
orange solid; mp 123−126 °C; H NMR (400 MHz, CDCl ): δ 9.12
s, 2 H), 8.39 (s, 1 H), 7.85 (d, J = 8.8 Hz, 4 H), 7.01 (d, J = 8.8 Hz, 4
H), 3.90 (s, 6 H); C NMR (100 MHz, CDCl ): δ 192.5, 164.0,
52.6, 137.5, 133.8, 132.6, 129.0, 114.1, 55.6; IR (KBr, cm ): 3065,
3
(
CDCl ): δ 192.6, 154.0, 152.5, 149.5, 137.6, 133.7, 129.1, 125.8, 111.7,
3
13
−1
3
110.1, 56.2, 56.1; IR (KBr, cm ): 3065, 2855, 1670, 1535, 810; ESI-
HRMS: Calcd for C H NO [M + H] 408.1447, found: 408.1443.
−1
1
2
3
+
23
22
6
+
855, 1670,1550, 790; ESI-HRMS: Calcd for C H NO [M + H] ,
21
18
4
3,5-Di(2-bromophenoyl) Pyridine (4n). Yield: 60 mg; 68%; yellow
48.1236, found: 348.1244.
,5-Di(4-dimethylaminophenoyl) Pyridine (4d). Yield: 42 mg;
1
solid; mp 123−125 °C; H NMR (400 MHz, CDCl ): δ 9.11 (s, 2 H),
3
3
13
8
.50 (s, 1 H), 7.68 (d, J = 8.0 Hz, 2 H), 7.51−7.41 (m, 6 H);
C
1
5
9
6%; gray solid; mp 100−102 °C; H NMR (400 MHz, CDCl ): δ
.05 (s, 2 H), 8.32 (s, 1 H), 7.79 (d, J = 9.2 Hz, 4 H), 6.69 (d, J = 9.2
Hz, 4 H), 3.10 (s, 12 H); C NMR (100 MHz, CDCl ): δ 191.9,
53.8, 151.4, 137.5, 134.6, 132.8, 123.6, 110.8, 40.1; IR (KBr, cm ):
3
NMR (100 MHz, CDCl ): δ 193.7, 154.8, 138.9, 137.7, 133.6, 132.3,
3
−1
1
5
4
30.5, 129.5, 127.8, 119.7; IR (KBr, cm ): 3050, 1665, 1580, 815,
50; ESI-HRMS: Calcd for C H Br NO [M + H] 443.9235, found:
13
+
3
−1
19 12
2
2
1
3
43.9231.
,5-Di(3,4-dichlorophenoyl) Pyridine (4o). Yield: 80 mg; 94%; gray
050, 2855, 1670, 1535, 810; ESI-HRMS: Calcd for C H N O [M +
23
24
3
2
3
+
H] 374.1869, found: 374.1876.
,5-Di(naphth-1-oyl) Pyridine (4e). Yield: 60 mg; 77%; brown
1
solid; mp 160−162 °C; H NMR (400 MHz, DMSO-d ): δ 9.15 (s, 2
6
3
H), 8.38 (s, 1 H), 8.06 (s, 2 H), 7.87 (d, J = 8.4 Hz, 2 H), 7.81 (d, J =
1
liquid; H NMR (400 MHz, CDCl ): δ 9.20 (s, 2 H), 8.59 (s, 1 H),
13
3
8
1
1
4
.4 Hz, 2 H); C NMR (100 MHz, DMSO-d ): δ 191.8, 153.0, 137.7,
36.3, 131.8, 131.7, 131.4, 131.1, 129.9; IR (KBr, cm ): 3065, 1670,
580, 815, 700; ESI-HRMS: Calcd for C H Cl NO [M + H]
6
8
7
.26−8.23 (m, 2 H), 8.03 (d, J = 8.0 Hz, 2 H), 7.93−7.91 (m, 2 H),
−1
.60 (d, J = 6.8 Hz, 2 H), 7.57−7.55 (m, 4 H), 7.49 (t, J = 7.6 Hz, 2
+
13
19 10
4
2
H); C NMR (100 MHz, CDCl ): δ 195.2, 154.4, 138.5, 134.2, 133.9,
3
23.9466, found: 423.9474.
,5-Di(3-nitrophenoyl) Pyridine (4p). Yield: 65 mg; 86%; yellow
1
32.9, 130.8, 129.2, 128.7, 128.5, 128.0, 126.9, 125.4, 124.3; IR (KBr,
3
−
1
cm ): 3055, 1670, 1585, 880, 750; ESI-HRMS: Calcd for C H NO
1
27
18
2
solid; mp 175−177 °C; H NMR (400 MHz, DMSO-d ): δ 9.20 (s, 2
+
6
[
M + H] 388.1338, found: 388.1342.
,5-Di(4-chlorophenoyl) Pyridine (4f). Yield: 66 mg; 93%; orange
H), 8.54 (d, J = 9.2 Hz, 4 H), 8.43 (s, 1 H), 8.28 (d, J = 7.6 Hz, 2 H),
3
7.89 (t, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, DMSO-d
): δ 192.5,
153.8, 148.4, 138.4, 137.8, 136.4, 132.2, 131.1, 128.0, 124.7; IR (KBr,
1
6
solid; mp 185−187 °C; H NMR (400 MHz, CDCl ): δ 9.17 (s, 2 H),
.44 (s, 1 H), 7.80 (d, J = 8.8 Hz, 4 H), 7.52 (d, J = 8.0 Hz, 4 H);
NMR (100 MHz, CDCl ): δ 192.5, 153.2, 140.3, 137.8, 134.4, 132.9,
31.4, 129.2; IR (KBr, cm ): 3055, 1670, 1580, 815, 710; ESI-HRMS:
3
13
8
C
−
1
cm ): 3055, 1675, 1590, 1530, 820; ESI-HRMS: Calcd for
3
+
−1
C
19
H
12
N
3
O
6
[M + H] 378.0726, found: 378.0731.
1
+
3,5-Dithiophen-2-oylpyridine (4q). Yield: 54 mg; 91%; brown
Calcd for C H Cl NO [M + H] 356.0245, found: 356.0255.
19
12
2
2
1
solid; mp 148−150 °C; H NMR (400 MHz, CDCl ): δ 9.26 (s, 2 H),
3
3
,5-Di(4-bromophenoyl) Pyridine (4g). Yield: 77 mg; 87%; gray
1
8.58 (s, 1 H), 7.84 (d, J = 4.8 Hz, 2 H), 7.70 (d, J = 3.6 Hz, 2 H), 7.24
solid; mp 201−202 °C; H NMR (400 MHz, CDCl ): δ 9.16 (s, 2 H),
3
13
13
(t, J = 4.8 Hz, 2 H); C NMR (100 MHz, CDCl
3
): δ 185.2, 152.4,
8
2
3
+
.44 (s, 1 H), 7.73−7.68 (m, 8 H); C NMR (100 MHz, CDCl ): δ19
3
−1
−1
142.6, 136.7, 135.8, 135.4, 133.6, 128.6; IR (KBr, cm ): 3120, 3020,
665, 1405, 710; ESI-HRMS: Calcd for C H NO S [M + H]
.7, 153.2, 137.9, 134.8, 132.8, 132.3, 131.4, 129.1; IR (KBr, cm ):
055, 1668, 1515, 805, 550; ESI-HRMS: Calcd for C H Br NO [M
+
1
15 10 2 2
19
12
2
2
+
300.0153, found: 300.0155.
H] 443.9235, found: 443.9236.
,5-Di(4-cyanophenoyl) Pyridine (4h). Yield: 42 mg; 62%; pale
3
,5-Di(naphth-2-oyl) Pyridine (4r). Yield: 45 mg, 58%; pale yellow
3
1
1
solid; mp 179−181 °C; H NMR (600 MHz, CDCl ): δ 9.32 (brs, 2
yellow solid; mp 172−174 °C; H NMR (400 MHz, CDCl ): δ 9.20
s, 2 H), 8.50 (s, 1 H), 7.95 (d, J = 8.4 Hz, 4 H), 7.88 (s, J = 8.0 Hz, 4
H); C NMR (100 MHz, CDCl ): δ 192.2, 153.8, 139.3, 137.9, 132.7,
32.1, 130.2, 117.5, 117.0; IR (KBr, cm ): 3060, 2250, 1675, 1510,
3
3
H), 8.62 (s, 1 H), 8.34 (s, 2 H), 8.02−7.94 (m, 8 H), 7.68 (t, 2 H, J =
(
8.4 Hz), 7.61 (t, 2 H, J = 8.4 Hz); 13C NMR (150 MHz, CDCl ): δ
13
3
3
−1
193.9, 153.2, 138.1, 135.7, 133.6, 132.4, 132.3, 129.6, 129.1, 129.0,
1
7
3
−1
+
127.9, 127.2, 125.5, 125.2; IR (KBr, cm ): 3050, 1667, 1510, 890,
90; ESI-HRMS: Calcd for C H N O [M + H] 338.0930, found:
21
12
3
2
+
7
3
30; ESI-HRMS: Calcd for C H NO [M + H] 388.1338, found:
38.0942.
,5-Di(4-trifluoromethylphenoyl) Pyridine (4i). Yield: 65 mg; 77%;
27 18 2
88.1332.
3-Benzoyl-5-(4-methoxyphenoyl) Pyridine (5a). Yield: 21 mg;
3%; ; pink liquid; H NMR (400 MHz, CDCl ): δ 9.15 (s, 1 H), 9.14
3
1
yellow solid; mp 108−110 °C; H NMR (400 MHz, CDCl ): δ 9.22
s, 2 H), 8.53 (s, 1 H), 7.95 (d, J = 8.0 Hz, 4 H), 7.83 (d, J = 8.0 Hz, 4
H); C NMR (100 MHz, CDCl ): δ 192.7, 153.8, 139.0, 138.0, 135.1,
34.8, 132.4, 130.2, 125.9 (q, J = 3.6 Hz), 124.7 (q, JC−F = 270 Hz);
3
1
3
(
3
13
(
s, 1 H), 8.44 (s, 1 H), 7.86−7.84 (m, 4 H), 7.66 (t, J = 7.2 Hz, 1 H),
3
1
3
7
.54 (t, J = 7.6 Hz, 2 H), 7.01 (d, J = 8.8 Hz, 2 H), 3.90 (s, 3 H);
): δ 194.0, 192.5, 164.1, 152.9, 152.8, 137.9,
136.3, 133.5, 132.6, 132.2, 130.0, 128.9, 128.8, 114.1, 113.7, 55.6; IR
C
1
C−F
−1
IR (KBr, cm ): 3060, 1670, 1555, 1250, 815; ESI-HRMS: Calcd for
NMR (100 MHz, CDCl
3
+
C H F NO [M + H] 424.0772, found: 424.0771.
2
1
12
6
2
−1
3
,5-Di(4-nitrophenoyl) Pyridine (4j). Yield: 63 mg; 84%; orange
(KBr, cm ): 3055, 2850, 1670, 1555, 815; ESI-HRMS: Calcd for
C
1
+
solid; mp 178−180 °C; H NMR (400 MHz, CDCl ): δ 9.23 (s, 2 H),
.54 (s, 1 H), 8.42 (d, J = 8.0 Hz, 4 H), 8.02 (d, J = 8.0 Hz, 4 H);
NMR (100 MHz, CDCl ): δ 192.0, 154.0, 150.6, 140.9, 137.9, 132.1,
30.8, 124.1; IR (KBr, cm ): 3055, 1670, 1590, 1530, 820; ESI-
20
H16NO
3
[M + H] : 318.1130, found: 318.1137.
3
13
8
C
3-(p-Toloyl)-5-(4-methoxyphenoyl) Pyridine (5b). Yield: 24 mg;
1
36%; orange solid; mp 178−180 °C; H NMR (400 MHz, CDCl ): δ
3
3
−1
1
9.13 (s, 2 H), 8.42 (s, 1 H), 7.85 (d, J = 8.8 Hz, 2 H), 7.75 (d, J = 8.4
Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.01 (d, J = 8.8 Hz, 2 H), 3.91 (s, 3
+
HRMS: Calcd for C H N O [M + H] 378.0726, found: 378.0736.
19
12
3
6
H), 2.46 (s, 3 H); 13C NMR (100 MHz, CDCl
): δ 194.1, 192.9,
164.5, 153.1, 145.1, 138.2, 134.1, 133.0, 132.6, 130.7, 130.5, 129.9,
3
,5-Di(2-methylphenoyl) Pyridine (4k). Yield: 41 mg; 65%; yellow
3
1
liquid; H NMR (400 MHz, CDCl ): δ 9.11 (s, 2 H), 8.50 (s, 1 H),
.46 (t, J = 6.8 Hz, 2 H), 7.35 (d, J = 6.4 Hz, 4 H), 7.29 (t, J = 7.6 Hz,
3
−1
7
129.5, 129.4, 114.5, 56.0, 22.1; IR (KBr, cm ): 3050, 2890, 2865,
9
875
dx.doi.org/10.1021/jo5018266 | J. Org. Chem. 2014, 79, 9872−9877

The Journal of Organic Chemistry
Note
+
1
675, 825; ESI-HRMS: Calcd for C H NO [M + H] : 332.1287,
21 18 3
ASSOCIATED CONTENT
Supporting Information
■
found: 332.1292.
*
S
3
-(p-Toloyl)-5-(4-nitrophenoyl) Pyridine (5c). Yield: 26 mg; 38%;
orange solid; mp 133−136 °C; H NMR (400 MHz, CDCl ): δ 9.19
s, 1 H), 9.17 (s, 1 H), 8.47 (s, 1 H), 8.40 (d, J = 8.8 Hz, 2 H), 8.00 (d,
General experimental information, copies of H and 13C NMR
spectra of all products, and CIF file containing crystallographic
data of 4b. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
1
3
(
J = 8.8 Hz, 2 H), 7.75 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H),
2
1
1
.48 (s, 3 H); 13C NMR (100 MHz, CDCl ): δ 193.1, 192.3, 154.0,
3
53.0, 150.4, 144.9, 141.2, 137.9, 133.6, 133.4, 130.8, 130.3, 129.6,
29.5, 124.0, 21.7; IR (KBr, cm ): 3050, 2890, 1670, 1530, 810; ESI-
HRMS: Calcd for C H N O [M + H] 347.1032, found: 347.1035.
−1
AUTHOR INFORMATION
+
■
20
15
2
4
Corresponding Author
*E-mail: wanjieping@jxnu.edu.cn (J.-P.W.).
3
-(p-Toloyl)-5-(thiophen-2-oyl) Pyridine (5d). Yield: 20 mg; 34%;
1
gray solid; mp 114−117 °C; H NMR (400 MHz, CDCl ): δ 9.16 (s, 1
3
H), 9.08 (s, 1 H), 8.42 (s, 1 H), 7.73−7.60 (m, 4 H), 7.25 (d, J = 8.0
Notes
Hz, 2 H),7.13 (t, J = 4.4 Hz, 1 H), 2.38 (s, 3 H); 13C NMR (100 MHz,
The authors declare no competing financial interest.
CDCl ): δ 193.5, 185.2, 153.1, 52.2, 144.7, 142.6, 137.3, 135.7, 135.4,
33.6, 133.4, 130.3, 129.5, 129.1, 128.5, 21.7; IR (KBr, cm ): 3130,
060, 2895, 1665, 810; ESI-HRMS: Calcd for C H NO S [M + H] :
08.0745, found: 308.0752.
-(4-Trifluoromethylphenoyl)-5-(4-nitrophenoyl) Pyridine (5e).
3
−1
1
3
3
+
ACKNOWLEDGMENTS
18
13
2
■
2
This work is generously supported by NSFC of China (no.
1102059) and a research program from the Department of
Education of Jiangxi Province (GJJ13245).
3
1
Yield: 26 mg; 32%; pale yellow solid; mp 114−117 °C; H NMR
400 MHz, CDCl ): δ 9.22 (s, 2 H), 8.53 (s, 1 H), 8.40 (d, J = 8.4 Hz,
(
3
2
8
1
1
H), 8.02 (d, J = 8.0 Hz, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.84 (d, J =
.0 Hz, 2 H); 13C NMR (100 MHz, CDCl ): δ 192.5, 192.1, 154.0,
REFERENCES
3
■
53.7, 150.5, 141.0, 138.9, 137.9, 135.1, 134.8, 132.4, 132.0, 130.8,
(1) For reviews on enaminone chemistry, see: (a) Greenhill, J. V.
Chem. Soc. Rev. 1977, 277. (b) Stanovnik, B.; Svete, J. Chem. Rev. 2004,
104, 2433. (c) Elassara, A. A.; El-Khairb, A. A. Tetrahedron 2003, 59,
8463. (d) Negri, G.; Kascheres, C.; Kascheres, A. J. J. Heterocycl. Chem.
2004, 41, 461.
30.2, 125.9 (q, J
= 3.5 Hz), 124.1, 122.0 (q, JC−F = 127 Hz); IR
C−F
−1
(
KBr, cm ): 3055, 1670, 1540, 1310, 805; ESI-HRMS: Calcd for
+
C H F N O [M + H] : 401.0749, found: 401.0752.
20
12
3
2
4
3
-(4-Cyanophenoyl)-5-(4-trifluoromethylphenoyl) Pyridine (5f).
1
Yield: 27 mg; 36%; pink solid; mp 124−126 °C; H NMR (400
MHz, CDCl ): δ 9.20 (s, 1 H), 9.19 (s, 1 H), 8.51 (s, 1 H), 7.95 (d,d, J
(2) For selected examples, see: (a) Jiang, B.; Li, Y.; Tu, M.-S.; Wang,
̃
S.-L.; Tu, S.-J.; Li, G. J. Org. Chem. 2012, 77, 7497. (b) Pena, R.;
3
=
8.8 Hz, J = 2.4 Hz, 4 H), 7.87 (d, J = 8.4 Hz, 2 H), 7.83 (d, J = 8.0
Jimen
́
ez-Alonso, S.; Feresin, G.; Tapia, A.; Men
́
dez-Alvarez, S.;
ez-Braun, A. J. Org. Chem. 2013, 78,
1
2
13
́
Machín, F.; Ravelo, A. G.; Estev
́
Hz, 2 H); C NMR (100 MHz, CDCl ): δ 192.5, 192.2, 153.9, 153.7,
3
7
977. (c) Guan, Z.-H.; Li, L.; Ren, Z.-H.; Li, J.; Zhao, M.-N. Green
Chem. 2011, 13, 1664. (d) Suryavanshi, P. A.; Sridharan, V.;
Menen
dez, J. C. Chem.Eur. J. 2013, 19, 13207. (e) Xiang, D.; Xin,
X.; Liu, X.; Zhang, R.; Yang, J.; Dong, D. Org. Lett. 2012, 14, 644.
3) (a) Wan, J.-P.; Lin, Y.; Hu, K.; Liu, Y. RSC Adv. 2014, 4, 20499.
1
1
39.4, 139.0, 137.9, 135.1, 134.8, 132.7, 132.5, 132.1, 130.2, 130.1,
25.9 (q, J = 3.8 Hz), 124.7 (q, JC−F = 274 Hz) 117.5, 117.0; IR
C−F
−1
́
(
KBr, cm ): 3055, 2885, 1665, 1350, 810; ESI-HRMS: Calcd for
+
C H F N O [M + H] : 381.0851, found: 381.0852.
21
12
3
2
2
(
3
-(2-Methylphenoyl)-5-(3-nitrophenoyl) Pyridine (5g). Yield: 31
1
(b) Elghamry, I. Synthesis 2003, 2301. (c) Abdel-Khalik, M. M.;
Elnagdi, M. H. Synth. Commun. 2002, 32, 159.
4) (a) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008,
mg; 45%; pale yellow solid; mp 114−117 °C; H NMR (400 MHz,
CDCl ): δ 9.18 (s, 2 H), 8.65 (s, 1 H), 8.51 (d, J = 8.0 Hz, 1 H), 8.48
3
(
1
(
t, J = 2.0 Hz, 1 H), 8.17 (d, J = 7.2 Hz, 1 H), 7.78 (t, J = 8.0 Hz, 1 H),
30, 3708. (b) Bi, L.; Georg, G. I. Org. Lett. 2011, 13, 5413. (c) Yu, Y.-
7
2
1
1
2
3
.47 (t, J = 7.6 Hz, 1 H), 7.38 (t, J = 8.8 Hz, 2 H), 7.33−7.29 (m, 1 H),
.44 (s, 3 H); 13C NMR (100 MHz, CDCl ): δ 195.4, 191.7, 154.6,
Y.; Niphakis, M. J.; Georg, G. I. Org. Lett. 2011, 13, 5932. (d) Kordik,
C. P.; Reitz, A. B. J. Org. Chem. 1996, 61, 5644. (e) Wan, J.-P.; Wang,
C.; Liu, Y. Org. Biomol. Chem. 2011, 9, 6481.
(5) (a) Edwankar, R. V.; Edwankar, C. R.; Namjoshi, O. A.;
Deschamps, J. R.; Cook, J. M. J. Nat. Prod. 2012, 75, 181. (b) Winkler,
J. D.; Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425. (c) Tsukanov, S.
V.; Comins, D. L. Angew. Chem., Int. Ed. 2011, 50, 8626.
3
53.5, 148.4, 138.0, 137.8, 137.6, 136.3, 135.2, 133.4, 131.9, 131.8,
31.7, 130.2, 129.2, 127.7, 125.6, 124.6, 20.3; IR (KBr, cm ): 3065,
880, 1670, 1540, 815; ESI-HRMS: Calcd for C H N O [M + H] :
47.1032, found: 347.1036.
-(3-Nitrophenoyl)-5-(3-methoxylphenoyl) Pyridine (5h). Yield:
−1
+
20
15
2
4
3
1
2
9 mg; 40%; orange solid; mp 90−92 °C; H NMR (400 MHz,
(
1
6) (a) Gibson, V. C.; Redshaw, C.; Solan, G. A. Chem. Rev. 2007,
07, 1745 and references cited therein. (b) Michael, J. P. Nat. Prod.
CDCl ): δ 9.23 (s, 1 H), 9.19 (s, 1 H), 8.67 (s, 1 H), 8.50 (t, J = 8.4
3
Hz, 2 H), 8.18 (d, J = 7.2 Hz, 1 H), 7.78 (t, J = 8.0 Hz, 1 H), 7.46−
Rep. 2005, 22, 627. (c) Redinbo, M. R.; Stewart, L.; Kuhn, P.;
Champoux, J. J.; Hol, W. G. J. Science 1998, 279, 1504. (d) Roughley,
S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
7) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
8) Vitale, M.; Ford, P. C. Coord. Chem. Rev. 2001, 219, 3.
(9) (a) Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem. Ber.
967, 100, 1094. (b) Nair, V.; Menon, R. S.; Sreekanth, A. R.;
Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520.
13
7.34 (m, 3 H), 7.20 (d, J = 8.0 Hz, 1 H), 3.88 (s, 3 H); C NMR (100
MHz, CDCl ): δ 193.3, 191.7, 160.0, 154.1, 153.1, 148.4, 137.9, 137.7,
3
1
1
37.3, 135.2, 133.2, 131.6, 130.2, 129.8, 127.7, 124.6, 122.8, 120.1,
14.3, 55.6; IR (KBr, cm ): 3055, 2885, 1670, 1535, 810; ESI-HRMS:
(
(
−1
+
Calcd for C H N O [M + H] , 363.0981, found: 363.0981.
20
15
2
5
3
-(3,4-Dichlorophenoyl)-5-(3,4-dimethoxylphenoyl) Pyridine (5i).
1
1
Yield: 34 mg; 41%; pink liquid; H NMR (400 MHz, CDCl ): δ 9.15
3
(
s, 1 H), 9.12 (s, 1 H), 8.40 (s, 1 H), 7.93 (s, 1 H), 7.67−7.60 (m, 2
(
10) (a) Pfister, J. R. Synthesis 1990, 689. (b) Zolfigol, M. A.; Shirini,
F.; Choghamarani, A. G.; Mohammadpoor-Baltork, I. Green Chem.
002, 4, 562.
H), 7.51 (s, 1 H), 7.34 (dd, J = 8.0 Hz, J = 2.4 Hz, 1 H), 6.92 (d, J =
1
2
13
8.8 Hz, 1 H), 3.97 (s, 3 H), 3.95 (s, 3 H); C NMR (100 MHz,
2
CDCl ): δ 192.1, 191.6, 154.1, 153.3, 152.5, 149.6, 138.3, 137.7, 135.8,
3
(11) For selected recent examples of pyridine synthesis, see:
(a) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc.
2007, 129, 10096. (b) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008,
130, 6918. (c) Shi, Z.; Loh, T.-P. Angew. Chem., Int. Ed. 2013, 52,
8584. (d) Ren, Z.-H.; Zhang, Z.-Y.; Yang, B.-Q.; Wang, Y.-Y.; Guan,
Z.-H. Org. Lett. 2011, 13, 5394. (e) Wu, Q.; Zhang, Y.; Cui, S. Org.
Lett. 2014, 16, 1350. (f) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J.
Org. Chem. 2012, 77, 2501.
1
5
33.9, 133.7, 132.1, 131.7, 131.0, 128.9, 126.4, 125.8, 111.7, 110.1,
6.2, 56.1; IR (KBr, cm ): 3065, 2880, 1675, 820, 720; ESI-HRMS:
−1
+
Calcd for C H Cl NO [M + H] 416.0456, found: 416.0450.
21
16
2
4
1
6
2
-(p-Methoxylbenzoyl)benzothiazole (8). Yield: 10 mg; 18%;
1
white solid; H NMR (400 MHz, CDCl ): δ 8.64 (d, 2 H, J = 8.0 Hz),
3
8
.22 (d, 1 H, J = 8.0 Hz), 8.00 (d, 1 H, J = 8.0 Hz), 7.59−7.50 (m, 2
H), 7.03 (d, 2 H, J = 8.0 Hz), 3.91 (s, 3 H).
9
876
dx.doi.org/10.1021/jo5018266 | J. Org. Chem. 2014, 79, 9872−9877

The Journal of Organic Chemistry
Note
(
12) Zhao, M.-N.; Hui, R.-R.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H.
Org. Lett. 2014, 16, 3082.
13) CCDC 1016422 (4b) contains the supplementary crystallo-
(
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(
(
14) Wasserman, H. H.; Ives, J. L. J. Org. Chem. 1985, 50, 3573.
15) For selected references on the domino reactions involving the
transamination process, see: (a) Wan, J.-P.; Lin, Y.; Huang, Q.; Liu, Y.
J. Org. Chem. 2014, 79, 7232. (b) Muthusaravanan, S.; Sasikumar, C.;
Devi bala, B.; Perumal, S. Green Chem. 2014, 16, 1297. (c) Cao, S.;
Jiang, Y.; Liu, Y.; Wan, J. Chin. J. Org. Chem. 2014, 34, 876 and
references cited therein.
(
16) Gao, Q.; Wu, X.; Jia, F.; Liu, M.; Zhu, Y.; Cai, Q.; Wu, A. J. Org.
Chem. 2013, 78, 2792.
9
877
dx.doi.org/10.1021/jo5018266 | J. Org. Chem. 2014, 79, 9872−9877