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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Direct synthesis of 2-methylpyridines via I2-triggered [3 + 2 + 1]
annulation of aryl methyl ketoxime acetates with triethylamine as
the carbon source
Received 00th January 20xx,
Accepted 00th January 20xx
Qinghe Gao,*a Huijuan Yan,a Manman Wu,a Jiajia Sun,a Xiqing Yan,a and Anxin Wub
DOI: 10.1039/x0xx00000x
www.rsc.org/
A facile and efficient [3 + 2 + 1] annulation of aryl methyl ketoxime acetates and triethylamine for the synthesis of 2-
methylpyridines was disclosed. This reaction demonstrated that I2 was effective to trigger N-O bond cleavage of oxime
acetates generating of imine radicals. It was noteworthy that this transformation employed triethylamine as the carbon
source
for
the
direct
formation
of
pyridines
and
introduction
of
methyl
groups.
been explored and represents an important area in need of
development. The Li group disclosed the first example of using
Et3N as the carbonyl source for constructing aryl methyl
ketone skeletons by palladium-catalyzed oxidative coupling of
aryl iodides with Et3N and water (Scheme 1a).9 Late on, Pan
Introduction
The so-called “magic methyl effect” makes 2-methylpyridines
very popular in many biologically active compounds,
pharmaceuticals, and agrochemicals.1 Meanwhile, 2-
methylpyridines are also employed as a class of fascinating
intermediates in organic and medicinal chemistry.2
Consequently, continued effort has been devoted to exploring
new and efficient strategies for the preparation of 2-
methylpyridine backbones. Recently, the C2-methylation
established
a copper-catalyzed direct and selective β-
sulfenylation of Et3N through a radical pathway, providing a
series of α,α-disulfenylated aldehydes (Scheme 1b).10 Jiang et
al. described a facile synthesis of 2-methyl-1,3,5-triazines via
aerobic copper-catalyzed cyclization of amidines, which was a
pioneering example of Et3N serving as the carbon source to
furnish heterocycles (Scheme 1c).11 Among these
transformations, single-electron oxidation of Et3N generating
the higher levels of reactivity of the iminium ion intermediate
in situ was a basic process. In this paper, based on our recent
study on I2-triggered reductive cleavage of the N-O bond,12 we
demonstrate a metal-free coulping reaction of ketoxime
acetate with the α-C(sp3)-H bond of TEA via convergent
integration of single-electron reduction and single-electron
oxidation (Scheme 1d).
reactions of pyridine N-oxides involving
a nucleophilic
addition/elimination mechanism by employing Tebbe’s
reagent, Grignard reagent, or diborylmethane as the methyl
sources have been reported by Nicolaou,3 Larionov,4 and Cho,5
respectively. Macmillan and co-workers discovered the direct
installation of the methyl group in pyridine with methanol by a
photoredox-induced radical reaction, although inseparable
regioisomeric mixtures were formed in some cases.6
Moreover, as an alternative, the introduction of methyl group
along with the construction of pyridine in one step would be
beneficial for the selectivity and diversity of the final product.7
Herein, we report a facile and efficient synthesis of 2-
methylpyridines from aryl methyl ketoxime acetates with
triethylamine (TEA) as the carbon source.
Scheme 1. TEA as the Carbon Sources via Oxidative Activation
of C-N Bond
O
I
H2O, PdCl2(MeCN)2
R
R
N
N
(a)
(b)
R
R
+
+
TBAB, ZnO
DMSO, 100 o
C
SH
S
N
S
Recently, cleaving the highly stable C-N bond in TEA and
applying the fragments to construct new C-N or C-C bonds
have aroused much attention.8 Whereas, compared to the
extensive studies of TEA as amino sources via oxidative
activation of C-N bond, its usage as carbon sources has rarely
CuI, O2
R
R
DMSO, 90 o
C
O
NH HCl
NH2
N
Cu(OAc)2, K3PO4, O2
toluene,100 o
(c)
(d)
N
N
+
C
R
R
NOAc
single-electron reduction
N
NOAc
Ar
Ar
N
Ar
Ar
Et3N, O2
1/2 I2
I
Ar
N
N
single-electron oxidation
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BPO (benzoyl peroxide), or H2O2 were added into the reaction
system respectively, and we found dioxygen worked most
efficiently (entries 2−6). However, only 36% of 3a was
obtained under a nitrogen atmosphere (entry 7). On the other
hand, investigation into the effect of the loading of I2 disclosed
that reducing the amount of I2 was negative to the results
(entries 9−11). Next, various solvents such as 1,4-dioxane,
CH3CN, NMP (N-methyl-2-pyrrolidinone), DMSO, DCE,
chlorobenzene, and DMF were screened (entries 12−18),
revealing that toluene was found to be still the most suitable
solvent for this transformation. Surprisingly, the yield of 3a
was improved to 72% on vigorous refluxing of the reaction
mixture in a 140 °C oil bath (entry 20). By replacing I2 with NIS
or NH4I, the desired product was isolated in 63% and 67%
yields, respectively (entries 22−23). However, no methylation
product was obtained in the presence of CuI, KI, or TBAI
(entries 24−26), and no reaction occurred in the absence of
iodine reagents, indicating that I2 is essential for the reaction
(entry 27). Moreover, varying the amount of TEA resulted in
reducing the reaction efficiency (entries 28−29).
Results and discussion
Initially, the reaction of 4-methylacetophenone oxime acetate
(
1a) with TEA (2a) was chosen as the model reaction using 1.5
Table 1. Optimization of Reaction Conditionsa
Entry [I] (equiv)
Oxidant
Solvent Temp. (°C) Yield (%)b
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
CH3CN
NMP
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
160
140
100
140
140
140
140
140
140
140
140
40
61
1
2
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (2.0)
I2 (1.0)
I2 (0.5)
I2 (0.2)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
NIS (1.5)
NH4I (1.5)
CuI (1.5)
KI (1.5)
TBAI (1.5)
O2
TBHP
DTBP
BPO
H2O2
Ar
trace
48
3
4
n.d.
n.d.
36
5
6
To evaluate the potential of amines to function as both the
carbon source and methylation reagent, other various tertiary
and secondary ethyl amines were further subjected to the
standard conditions optimized for 2a. As shown in Table 2,
even though N,N-diethylaniline (2b) could afford 3a in 54%
yield, other ethyl amines were ineffective. These results clearly
illustrated that the choice of amines was crucial for this
annulation process.
7
O2
60
8
O2
50
9
O2
23
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28c
29d
O2
trace
42
O2
Table 2. Representative Ethyl Amines
O2
51
O2
trace
n.d.
n.r.
12
O2
DMSO
O2
DCE
O2
PhCl
O2
DMF
17
O2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
55
O2
72
With the optimized reaction conditions in hand, the
generality and scope of this efficient I2-triggered [3 + 2 + 1]
annulation of ketoxime acetates and TEA for the introduction
of methyl groups was explored. It was revealed that this
reaction featureed wide substrate scope of the ketoxime
acetates (Scheme 2). Aryl methyl ketone O-acetyloximes
bearing both electron-neutral (e.g., 4-Me, 3-Me, 2-Me, 4-Et, 4-
t-Bu, 4-H) and electron-donating (e.g., 4-OMe, 4-OEt, 3,4-
OCH2O) on the aromatic rings were converted to the
corresponding 2-methylpyridines in moderate to good yields
O2
15
O2
63
O2
67
O2
n.d.
n.r.
n.r.
n.r.
39
O2
O2
O2
O2
(57−84%; 3a
−
3i). These results suggested the steric effect
3b, and 3c). Much to our
I2 (1.5)
played a role in the reaction (3a
,
I2 (1.5)
O2
17
satisfaction, the optimized conditions were mild enough to be
compatible with a broad range of halogenated (e.g., 4-F, 4-Cl,
4-Br, 3,4-Cl2) substrates (50−61%; 3j−3m), providing enormous
aReaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), I2 (0.75
mmol), oxidant (1.0 mmol), solvent (2 mL). bIsolated yield; n.d.
= no desired product; n.r. = no reaction. c2a (1.5 mmol). d2a
(0.5 mmol).
possibilities for further modification. Notably, the
acetophenone oxime acetates with strongly electron-
withdrawing groups 4-CF3 and 3-NO2 could be accessed
through this route to generate the desired products in a
equiv of I2 in toluene at 120 °C (Table 1). To our delight, the
methyl-containing pyridine (3a) was obtained albeit in
moderate yield (entry 1). This reaction indicated that cleavage
of N-O bond in oxime acetates and C-N bond in TEA occurred
in the presence of I2. Subsequently, oxidants including O2,
slightly low yield (46−55%; 3n
−3o). When β-naphthyl methyl
ketoxime acetate was used as the substrate, the expected
TBHP (tert-butyl hydroperoxide), DTBP (di-tert-butyl peroxide), product (3p) could be isolated in 47% yield. In addition, the
2 | J. Name., 2012, 00, 1-3
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optimized conditions could be applied to thiophene-2-yl metaldehyde (3.0 equiv) instead of a part of TEA was subjected
methyl ketoxime acetate and thiophene-3-yl methyl ketoxime to this reaction system, a low yield of 3a was obtained
acetate, delivering the annulation products in 82% and 66% (Scheme 3b), which might be due to the higher levels of
yields, respectively (3q−3r). It is noteworthy that ketoxime reactivity of the iminium ion intermediate in situ generated.
acetate derived from α-tetralone underwent the desired When acetophenone was added to the reaction mixture, the
reaction to afford the symmetrical 4-methylpyridine (3s) in 3a was still obtained in 68% yield, but the pyridine (5) was not
excellent yield (91%). Unfortunately, no reaction took place observed. This result demonstrated that the corresponding
when alkyl ketoxime acetates such as 3,3-dimethylbutan-2-one ketone was only the byproduct rather than the electrophile or
oxime acetates were employed as the substrate. Furthermore, intermediate in the reaction (Scheme 3c). In addition, we
tribenzylamine (2f) was also a good substrate for the reaction investigated the cross-coupling reaction between two
to form the desired 2-phenylpyridine (3t). However, no representative substrates 4-methylacetophenone oxime
expected product was detected when N,N-dimethylaniline acetate (1a) and acetophenone oxime acetate (1f) under
(
2g), trimethylamine (25% in H2O) (2h), or tripropylamine (2i
)
standard conditions. Fortunately, all the products were
was submitted to the standard conditions. It is regrettable that successfully identified by HRMS analysis of the crude reaction
this valuable tool did not install another alkyl onto the pyridine extract (Scheme 3d).
ring.
Scheme 2. Scope of Ketoxime Acetates and Tertiary Aminesa
Scheme 3. Control Experiments
We further experimented to develop a better understanding
of the reaction mechanism by performing 13C-labeling and D-
labeling experiments under the optimized conditions using
acetophenone-β,β,β-d3 oxime acetate and acetophenone-β-13C
oxime acetate, respectively, as substrates. The corresponding
desired products 3f’ and 3f-d2 were obtained in 82% and 79%
yields, respectively (Scheme 4a and 4b). These experimental
results strongly suggested that methyl ketone O-acetyloximes
provided four carbons to form the pyridine ring. Then, the
speculation that the α-C of TEA was integrated into the final
pyridines has been demonstrated when TEA-d15 was used in
this reaction system (Scheme 4c). In addition, both of the
deuterated experimental evidences are in agreement with the
observation of internal D/H exchange in the 2-methylpyridines.
Scheme 4. 13C-Labeling and D-Labeling Experiments
aReaction conditions: 1 (0.5 mmol), 2a (1.0 mmol) and I2 (0.75 mmol)
in toluene (2 mL) under oxygen balloon at 140 °C. Isolated yield.
bConducted on 10 mmol scale, isolated yield.
As we proposed above, this I2-triggered coulping/cyclization
might undergo radical process. Indeed, the inhibiton
experiments of radical showed that TEMPO completely
suppressed the reaction, and the yield of 3a was reduced
significantly in the presence of BHT (Scheme 3a). These results
supported the proposed radical process via single electron
transfer. The oxidation of TEA formed the iminium ion, which
may generate in situ the acetaldehyde. However, when
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as both the carbon source and electron donor in the reaction.
Significantly, the method opens up a new strategy for I2-
induced transformation of oxime esters.
Experimental
General information
All substrates and reagents were commercially available and used
without further purification. TLC analysis was performed using pre-
coated glass plates. Column chromatography was performed using
silica gel (200–300 mesh). 1H spectra were recorded in CDCl3 on 400
MHz NMR spectrometers and resonances (δ) are given in parts per
million relative to tetramethylsilane. 13C spectra were recorded in
CDCl3 on 100 MHz NMR spectrometers and resonances (δ) are given
in ppm. HRMS were obtained on a Bruker 7-tesla FT-ICR MS
equipped with an electrospray source. Melting points were
determined using XT-4 apparatus and not corrected.
On the basis of the results in the current study and previous
reports,13 a possible mechanism has been proposed using
acetophenone oxime acetate (1f) and TEA (2a) as examples
(Scheme 5). Initially, the single-electron-transfer(SET)
reduction of the N-O bond of oxime acetate 1f with molecular
iodine or iodine radical produced the hypervalent iodine
General procedure for the synthesis of 3
A mixture of oxime acetates 1 (0.5 mmol), iodine (0.75 mmol), and
species (I+) and an iminyl radical intermediate A 14
reductively quenched by Et3N to produce the corresponding
anion B 15
Then, the imine-type intermediate was formed
from 2a via a SET oxidative process.16 Subsequently, the
nucleophilic attack of by intermediate resulted in the
formation of intermediate . Next, the enamine intermediate
quickly generated from the tautomerization of
,
which was
Et3N (1.0 mmol) in toluene (2 mL) was stirred under oxygen balloon
o
at 140 C. After disappearance of the reactant (monitored by TLC),
and added 50 mL water to the mixture, then extracted with EtOAc 3
times (3 × 50 mL). The extract was washed with 10% Na2S2O3
solution (w/w), dried over anhydrous Na2SO4 and evaporation. The
residue was purified by column chromatography on silica gel
(eluent: petroleum ether/EtOAc) to afford the product 3.
.
D
D
B
E
F
E
reacted with a
2-methyl-4,6-di-p-tolylpyridine (3a):
second molecular of ketoxime acetate 1f to give the
intermediate followed by the release of NH2OAc to afford
Finally, the intermediate underwent sequential
intramolecular deamination cyclization and oxidative
o
1
G
H.
Yield 72% (49.1 mg); pink solid; mp 91–94 C; H NMR (400 MHz,
I
CDCl3): δ (ppm) 7.92 (d, J = 8.0 Hz, 2H), 7.68 (s, 1H), 7.57 (d, J = 7.6
Hz, 2H), 7.33–7.24 (m, 5H), 2.67 (s, 3H), 2.41 (s, 3H), 2.40 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ (ppm) 158.6, 157.5, 149.3, 138.8, 138.6,
137.1, 135.9, 129.7, 129.4, 127.0, 126.9, 119.3, 115.6, 24.8, 21.3,
21.2; HRMS (ESI): m/z [M + Na]+ calcd for C20H19NNa: 296.1410;
found: 296.1410.
aromatization reactions to provide the desired product 3f
Scheme 5. Proposed Mechanism
.
2-methyl-4,6-di-m-tolylpyridine (3b):
1
Yield 68% (46.4 mg); brown oil; H NMR (400 MHz, CDCl3): δ (ppm)
7.86 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.69 (s, 1H), 7.47 (d, J = 7.6 Hz,
2H), 7.40–7.33 (m, 2H), 7.30 (s, 1H), 7.24 (t, J = 8.8 Hz, 2H), 2.69 (s,
3H), 2.45 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 158.6, 157.8,
149.6, 139.8, 138.8, 138.7, 138.3, 129.6, 129.5, 128.9, 128.6,
127.8(4), 127.7(9), 124.2(4), 124.1(8), 119.7, 116.2, 24.8, 21.5(4),
21.4(9); HRMS (ESI): m/z [M + H]+ calcd for C20H20N: 274.1590;
found: 274.1590.
2-methyl-4,6-di-o-tolylpyridine (3c):
1
Yield 57% (38.9 mg); red oil; H NMR (400 MHz, CDCl3): δ (ppm)
7.45–7.41 (m, 1H), 7.32–7.24 (m, 7H), 7.17 (s, 1H), 7.09 (s, 1H), 2.67
(s, 3H), 2.40 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
159.2, 157.7, 150.1, 140.6, 139.5, 135.7, 135.0, 130.7, 130.6, 129.6,
129.3, 128.2, 128.1, 126.0, 125.9, 121.7(0), 121.6(5), 24.7, 20.3(7),
20.3(5); HRMS (ESI): m/z [M + H]+ calcd for C20H20N: 274.1590;
found: 274.1590.
Conclusions
In summary, we have developed a facile and efficient I2-
triggered [3 + 2 + 1] annulation of aryl methyl ketoxime
acetates and triethylamine to produce diverse 2-
methylpyridines which are challenging to prepare by
traditional methods. This strategy is based on convergent
integration of single-electron reduction and single-electron
oxidation for the N-O/C-N bond cleavages along with the
sequential activation of Csp3-H bond. Triethylamine performed
2,4-bis(4-ethylphenyl)-6-methylpyridine (3d):
1
Yield 73% (54.9 mg); pink oil; H NMR (400 MHz, CDCl3): δ (ppm)
7.94 (d, J = 8.4 Hz, 2H), 7.69 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.34–
7.27 (m, 5H), 2.76–2.69 (m, 4H), 2.67 (s, 3H), 1.32–1.24 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 158.6, 157.6, 149.3, 145.2, 145.0,
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137.4, 136.2, 128.5, 128.2, 127.1, 127.0, 119.3, 115.7, 28.7, 28.6, 2,4-bis(4-bromophenyl)-6-methylpyridine (3l):
24.8, 15.6, 15.5; HRMS (ESI): m/z [M + Na]+ calcd for C22H23NNa:
324.1723; found: 324.1724.
o
1
Yield 53% (53.4 mg); light yellow solid; mp 146–148 C; H NMR
(400 MHz, CDCl3): 7.91 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.8 Hz, 4H),
7.59 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 2.68 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 159.2, 156.5, 148.5, 138.4, 137.5,
132.2, 131.8, 128.7, 128.6, 123.4, 119.8, 115.5, 24.8; HRMS (ESI):
m/z [M + H]+ calcd for C18H14Br2N: 401.9488; found: 401.9486.
2,4-bis(4-(tert-butyl)phenyl)-6-methylpyridine (3e):
o
1
Yield 69% (61.6 mg); brown solid; mp 83–86 C; H NMR (400 MHz,
CDCl3): δ (ppm) 7.94 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.62 (d, J = 8.0
Hz, 2H), 7.54–7.47 (m, 4H), 7.29 (s, 1H), 2.68 (s, 3H), 1.38 (s, 9H),
1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 158.6, 157.6, 152.1, 2,4-bis(3,4-dichlorophenyl)-6-methylpyridine (3m):
o
1
151.9, 149.2, 137.1, 135.9, 126.9, 126.7, 126.0, 125.6, 119.4, 115.8,
34.6(9), 34.6(5), 31.3(0), 31.2(9), 24.8; HRMS (ESI): m/z [M + H]+
calcd for C26H32N: 358.2529; found: 358.2527.
Yield 50% (47.9 mg); pink solid; mp 165–168 C; H NMR (400 MHz,
CDCl3): δ (ppm) 8.16 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.4, 2.0 Hz, 1H),
7.75 (d, J = 2.0 Hz, 1H), 7.61 (s, 1H), 7.60–7.52 (m, 2H), 7.49 (dd, J =
8.4, 2.0 Hz, 1H), 7.29 (s, 1H), 2.72 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 159.5, 155.2, 147.5, 139.0, 138.3, 133.5, 133.4, 133.3,
133.0(5), 131.0(9), 130.7, 129.0, 128.9, 126.3, 126.2, 120.2, 115.5,
24.7; HRMS (ESI): m/z [M + H]+ calcd for C18H12Cl4N: 381.9718;
found: 381.9718.
2-methyl-4,6-diphenylpyridine (3f):
o
1
Yield 84% (51.4 mg); pink solid; mp 68–70 C; H NMR (400 MHz,
CDCl3): δ (ppm) 8.03 (d, J = 7.2 Hz, 2H), 7.72 (s, 1H), 7.71–7.65 (m,
2H), 7.54–7.39 (m, 6H), 7.33 (s, 1H), 2.70 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 158.8, 157.7, 149.5, 139.8, 138.8, 129.0, 128.9,
128.8, 128.7, 127.1(4), 127.0(9), 119.8, 116.2, 24.8; HRMS (ESI): m/z 2-methyl-4,6-bis(4-(trifluoromethyl)phenyl)pyridine (3n):
[M + H]+ calcd for C18H16N: 246.1277; found: 246.1277.
o
1
Yield 55% (52.4 mg); pink solid; mp 100–103 C; H NMR (400 MHz,
CDCl3): δ (ppm) 8.16 (d, J = 8.0 Hz, 2H), 7.77 (s, 4H), 7.74 (d, J = 6.8
Hz, 3H), 7.37 (s, 1H), 2.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
159.6, 156.3, 148.4, 142.7, 142.1, 131.2, 131.0, 130.9, 130.7, 127.5,
127.4, 126.1(3), 126.0(9), 126.0(5), 126.0, 125.8, 125.7(1), 125.6(8),
125.6, 125.5, 125.3, 122.8, 122.6, 120.7, 116.4, 24.8; HRMS (ESI):
m/z [M + H]+ calcd for C20H14F6N: 382.1025; found: 382.1029.
2,4-bis(4-methoxyphenyl)-6-methylpyridine (3g):
o
1
Yield 69% (52.6 mg); yellow solid; mp 95–97 C; H NMR (400 MHz,
CDCl3): δ (ppm) 7.98 (d, J = 8.8 Hz, 2H), 7.64–7.58 (m, 3H), 7.21 (s,
1H), 6.99 (d, J = 8.8 Hz, 4H), 3.84 (s, 6H), 2.64 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 160.2(3), 160.2(1), 158.5, 157.1, 148.8, 132.5,
131.1, 128.3, 128.1, 118.6, 114.8, 114.3, 114.0, 55.2(9), 55.2(6),
24.7; HRMS (ESI): m/z [M + H]+ calcd for C20H20NO2: 306.1489; 2-methyl-4,6-bis(3-nitrophenyl)pyridine (3o):
Yield 46% (38.5 mg); white solid; mp 205–208 oC; 1H NMR (400 MHz,
found: 306.1492.
2,4-bis(4-ethoxyphenyl)-6-methylpyridine (3h):
CDCl3): δ (ppm) 8.94 (s, 1H), 8.55 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H),
8.37–8.28 (m, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.78–7.66 (m,
2H), 7.45 (s, 1H), 2.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
160.1, 155.3, 148.9, 148.8, 147.6, 140.9, 140.1, 133.0, 132.9, 130.3,
129.8, 123.8(4), 123.7(8), 122.1(0), 122.0(5), 120.9, 115.9, 24.8;
HRMS (ESI): m/z [M + Na]+ calcd for C18H13N3NaO4: 358.0798; found:
358.0796.
o
1
Yield 62% (51.6 mg); brown solid; mp 107–110 C; H NMR (400
MHz, CDCl3): δ (ppm) 7.97 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 3H),
7.22 (s, 1H), 7.02–6.96 (m, 4H), 4.08 (q, J = 6.8 Hz, 4H), 2.65 (s, 3H),
1.48–1.40 (m, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 159.6(8),
159.6(5), 158.4, 157.2, 148.9, 132.3, 130.9, 128.3, 128.1, 118.5,
114.9, 114.8, 114.6, 63.6, 63.5, 24.7, 14.7(9), 14.7(7); HRMS (ESI):
m/z [M + H]+ calcd for C22H24NO2: 334.1802; found: 334.1806.
2-methyl-4,6-di(naphthalen-2-yl)pyridine (3p):
2,4-bis(benzo[d][1,3]dioxol-5-yl)-6-methylpyridine (3i):
Yield 47% (40.5 mg); white solid; mp 239–241 oC; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.55 (s, 1H), 8.22 (dd, J = 8.4, 1.6 Hz, 1H), 8.17 (s,
1H), 7.99–7.92 (m, 5H), 7.91–7.83 (m, 2H), 7.81 (dd, J = 8.8, 1.6 Hz,
1H), 7.58–7.48 (m, 4H), 7.45 (s, 1H), 2.76 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 159.0, 157.5, 149.4, 137.1, 136.1, 133.6, 133.5(2),
133.4(7), 133.4, 128.8, 128.7, 128.4(x 2), 127.7(1), 127.6(5), 126.7,
126.6, 126.4(4), 126.3(8), 126.3(7), 126.2, 124.9, 124.8, 120.0, 116.5,
24.9; HRMS (ESI): m/z [M + Na]+ calcd for C26H19NNa: 368.1410;
found: 368.1409.
o
1
Yield 70% (58.3 mg); yellow solid; mp 145–148 C; H NMR (400
MHz, CDCl3): δ (ppm) 7.56–7.50 (m, 3H), 7.21–7.12 (m, 3H), 6.93–
6.87 (m, 2H), 6.02 (s, 2H), 6.00 (s, 2H), 2.64 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 158.6, 157.0, 149.0, 148.4, 148.3(0), 148.2(6),
148.1, 134.3, 132.9, 121.0, 120.9, 119.0, 115.1, 108.7, 108.4, 107.6,
107.3, 101.4, 101.2, 24.74; HRMS (ESI): m/z [M + H]+ calcd for
C20H16NO4: 334.1074; found: 334.1073.
2,4-bis(4-fluorophenyl)-6-methylpyridine (3j):
2-methyl-4,6-di(thiophen-2-yl)pyridine (3q):
o
1
Yield 58% (40.7 mg); pink solid; mp 95–98 C; H NMR (400 MHz,
CDCl3): δ (ppm) 8.06–7.96 (m, 2H), 7.68–7.59 (m, 3H), 7.26 (s, 1H),
7.17 (q, J = 8.8 Hz, 4H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 164.7, 164.6, 162.2, 162.1, 159.0, 156.6, 148.6, 135.8, 134.8,
128.9, 128.8(4), 128.7(6) 119.6, 116.1, 115.9, 115.7, 115.6, 115.5,
24.8; HRMS (ESI): m/z [M + H]+ calcd for C18H14F2N: 282.1089; found:
282.1088.
1
Yield 82% (52.7 mg); brown oil; H NMR (400 MHz, CDCl3): δ (ppm)
7.68–7.60 (m, 2H), 7.52 (dd, J = 4.0, 1.2 Hz, 1H), 7.44–7.36 (m, 2H),
7.21 (s, 1H), 7.17–7.08 (m, 2H), 2.60 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 159.0, 152.6, 144.8, 142.3, 141.5, 128.3, 127.9,
127.4, 126.9, 125.2, 124.6, 117.9, 112.5, 24.5; HRMS (ESI): m/z [M +
H]+ calcd for C14H12NS2: 258.0406; found: 258.0408.
2-methyl-4,6-di(thiophen-3-yl)pyridine (3r):
2,4-bis(4-chlorophenyl)-6-methylpyridine (3k):
o
1
Yield 61% (47.7 mg); white solid; mp 130–133 oC; 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.97 (d, J = 8.4 Hz, 2H), 7.63 (s, 1H), 7.59 (d, J = 8.4
Hz, 2H), 7.45 (t, J = 8.4 Hz, 4H), 7.28 (s, 1H), 2.68 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 159.2, 156.5, 148.4, 138.0, 137.1, 135.2,
135.0, 129.3, 128.9, 128.4, 128.3, 119.8, 115.6, 24.8; HRMS (ESI):
m/z [M + H]+ calcd for C18H14Cl2N: 314.0498; found: 314.0495.
Yield 66% (42.4 mg); yellow solid; mp 68–71 C; H NMR (400 MHz,
CDCl3): δ (ppm) 7.95 (d, J = 2.0 Hz, 1H), 7.71–7.65 (m, 2H), 7.60 (s,
1H), 7.49–7.43 (m, 2H), 7.40 (dd, J = 4.8, 2.8 Hz, 1H), 7.25 (s, 1H),
2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 158.9, 153.6, 143.8,
142.3, 140.0, 126.9, 126.4, 126.2, 125.9, 123.7, 122.8, 118.7, 115.0,
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DOI: 10.1039/C8OB00349A
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Journal Name
24.7; HRMS (ESI): m/z [M + H]+ calcd for C14H12NS2: 258.0406; found:
258.0407.
12 Q. Gao, Z. Liu, Y. Wang, X. Wu, J. Zhang and A. Wu, Adv.
Synth. Catal., 2018, 10.1002/adsc.201701610.
13 (a) S. A. Girard, T. Knauber and C.-J. Li, Angew. Chem. Int. Ed.,
2014, 53, 74; (b) P. Finkbeiner and B. J. Nachtsheim,
Synthesis, 2013, 45, 979; (c) G. Yin, Q. Liu, J. Ma and N. She,
Green Chem., 2012, 14, 1796; (d) D. Liu and A. Lei, Chem.
Asian J., 2015, 10, 806; (e) J. Li, Y. Hu, D. Zhang, Q. Liu, Y.
Dong and H. Liu, Adv. Synth. Catal., 2017, 359, 710; (f) X.
Chen, T. Chen, Y. Zhou, D. Han, L.-B. Han and S.-F. Yin, Org.
Biomol. Chem., 2014, 12, 3802; (g) H. Huang, X. Ji, W. Wu
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7-methyl-5,6,8,9-tetrahydrodibenzo[c,h]acridine (3s):
o
1
Yield 91% (67.6 mg); brown solid; mp 185–189 C; H NMR (400
MHz, CDCl3): δ (ppm) 8.57 (dd, J = 7.6, 0.8 Hz, 2H), 7.45–7.39 (m,
2H), 7.36–7.30 (m, 2H), 7.26 (d, J = 7.2 Hz, 2H), 2.99 (s, 8H), 2.34 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 149.3, 137.5, 135.4, 129.5,
129.5, 128.4, 127.3, 126.9, 125.3, 28.0, 24.6, 14.6; HRMS (ESI): m/z
[M + H]+ calcd for C22H20N: 298.1590; found: 298.1595.
2-phenyl-4,6-di-p-tolylpyridine (3t):
Chem. Front., 2017, 4, 597; (i) H. Batchu, S. Bhattacharyya
o
1
Yield 79% (66.2 mg); yellow solid; mp 69–72 C; H NMR (400 MHz,
CDCl3): δ (ppm) 8.10 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.73 (d, J = 7.2
Hz, 1H), 7.54–7.44 (m, 2H), 7.40 (d, J = 7.2 Hz, 3H), 7.34–7.27 (m,
5H), 7.22–7.18 (m, 1H), 3.54 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 157.4, 150.0, 139.6, 139.2, 138.9, 136.9, 129.4,
129.0, 128.8, 128.7, 128.2, 127.2, 127.0, 126.8, 116.5, 57.9, 21.3;
HRMS (ESI): m/z [M + Na]+ calcd for C25H21NNa: 358.1566; found:
358.1573.
and S. Batra, Org. Lett., 2012, 14, 6330; (j) W.-C. Gao, F. Hu,
Y.-M. Huo, H.-H. Chang, X, Li and W.-L. Wei, Org. Lett., 2015,
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Zha and Z. Wang, Angew. Chem. Int. Ed., 2012, 51, 8077; (b)
S. Tang, K. Liu, Y. Long, X. Gao, M. Gao and A. Lei, Org. Lett.,
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(b) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan and A. Lei,
Angew. Chem. Int. Ed., 2014, 53, 502; (c) E. Speckmeier, C.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant 21605127). This work was also
supported by the Xinxiang Innovative Technology Team (Grant
16 (a) C. Rao, S. Mai and Q. Song, Org. Lett., 2017, 19, 4726; (b)
T. Nobuta, N. Tada, A. Fujiya, A. Kariya, T. Miura and A. Itoh,
Org. Lett., 2013, 15, 574; (c) H.-M. Huang, Y.-J. Li, Q. Ye, W.-
B. Yu, L. Han, J.-H. Jia and J.-R. Gao, J. Org. Chem., 2014, 79,
1084; (d) J.-S. Tian, K. Wai, J. Ng, J.-R. Wong and T.-P. Loh,
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CXTD17004). Dr. X. Yan acknowledge the Scientific
&
Technological
Project
of
Henan
Province
(Grant
172102310616).
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6 | J. Name., 2012, 00, 1-3
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