Lewis-acid-catalyzed benzylic reactions of 2-methylazaarenes with aldehydes

Article abstract of DOI:10.1002/ejoc.201400073

Lewis-acid-catalyzed benzylic reactions of 2-methylazaarenes with aldehydes have been investigated. Series of azaarene derivatives were afforded by this reaction. 2-(Pyridin-2-yl)ethanols with common substituents were formed through the LiNTf₂-promoted aldol reaction for the first time. 2-Alkenylpyridines, exclusively in the form of the E isomers, were synthesized in the presence of LiNTf₂ cooperated with H₂NTf. In the presence of La(Pfb)₃ as catalysis, 2-alkenylquinolines were obtained in high yields through the reactions between 2-methylquinolines and aldehydes under air.

Full text of DOI:10.1002/ejoc.201400073

Job/Unit: O40073
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FULL PAPER
DOI: 10.1002/ejoc.201400073
Lewis-Acid-Catalyzed Benzylic Reactions of 2-Methylazaarenes with Aldehydes
Dan Mao,[a] Gang Hong,[a] Shengying Wu,[a] Xin Liu,[a] Jianjun Yu,[a] and Limin Wang*[a]
Keywords: Nitrogen heterocycles / Aldol reactions / C–H activation
Lewis-acid-catalyzed benzylic reactions of 2-methylazaar-
enes with aldehydes have been investigated. Series of azaar-
ene derivatives were afforded by this reaction. 2-(Pyridin-2-
yl)ethanols with common substituents were formed through
the LiNTf2-promoted aldol reaction for the first time. 2-Alk-
enylpyridines, exclusively in the form of the E isomers, were
synthesized in the presence of LiNTf2 cooperated with
H2NTf. In the presence of La(Pfb)3 as catalysis, 2-alkenyl-
quinolines were obtained in high yields through the reac-
tions between 2-methylquinolines and aldehydes under air.
alkaloids found particularly in lobelia and sedum alkaloids,
and are widely used as drugs.[3] In addition, 2-alkenylyridine
Introduction
The pyridine moiety is a privileged structure that is ubiqui- derivatives are not only ubiquitous structural motifs in bio-
tous in nature.[1] Therefore, functionalized pyridines and re- logically relevant molecules – for example, CGS23114 (4) –
lated azaarenes play increasingly important roles in natural but also serve as valuable precursors for a wide range of
compounds synthesis and drug discovery.[2] Among them, 2-alkylpyridines and piperidines, themselves of significant
as depicted in Figure 1, 2-(pyridin-2-yl)ethanols are precur- biological importance,[4] whereas 2-alkenylquinolines, espe-
sors of sedamine (1), lobeline (2), and lobenlanidine (3), cially those containing the (7-chloroquinolin-2-yl)vin-
which are members of a large and diverse group of ylphenyl moiety, are always present in the leukotriene recep-
Figure 1. Biologically important 2-(pyridin-2-yl)ethanol and 2-alkenylazaarene derivatives.
tor antagonists (LTRAs), such as montelukast (5), L-
[a] Key Laboratory for Advanced Materials and Institute of Fine
660,711 (6), and LY290154 (7), used for the treatment of
Chemicals, East China University of Science and Technology,
asthma.[5]
130 Meilong Road, Shanghai 200237, P. R. China
E-mail: wanglimin@ecust.edu.cn
It is not surprising, therefore, that great efforts have been
directed toward developing synthetic approaches for the
construction of derivatives of pyridine and other aza-
http://hyxy.ecust.edu.cn/new/viewProf.php?id=249
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400073.
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D. Mao, G. Hong, S. Wu, X. Liu, J. Yu, L. Wang
FULL PAPER
arenes.[6] However, due to their inherent π-electron-deficient for improving the yield (Entries 2–7). Next, a series of cata-
nature, low reactivity of pyridine and related azaarene rings lysts including inorganic acid and base (Entries 9 and 10),
toward aromatic electrophilic substitution reactions has traditional Lewis acids (Entries 10–14), and other rare earth
been observed. Traditionally, pyridine N-oxide and N- triflates (Entries 15–17) were tried in order to improve the
iminopyridinium ylides have been successfully used as alter- yields of the product, but none was better than Sc(OTf)3.
native substrates to enhance the acidity of C2-H[7] and also Previously, we reported that rare earth pentafluorobenzo-
the C(sp3)-H protons of 2-methylpyridines.[8] However, ad- ates [RE(Pfb)3] were effective Lewis acids for condensation
ditional steps were needed to introduce the activation reactions.[16a,16g] We therefore applied Sc(Pfb)3 and La-
groups in these reactions.
(Pfb)3 in this reaction. Disappointingly, only trace product
Recently, direct C(sp3)–H bond functionalization of 2- was detected in both cases (Entries 18 and 19). To our de-
alkyl-substituted azaarenes catalyzed by palladium,[9] Lewis light, though, when the rarely used Lewis acid lithium
acids,[10] Brønsted acids,[11] or iodine,[12] or even without bis[(trifluoromethyl)sulfonyl]amide (LiNTf2)[17] was em-
catalyst,[13] has been widely used to synthesize azaarene de- ployed, the yield of 3aa was increased to 52% (Entry 20).
rivatives. The electrophilic reagents included C=N double Further investigation found that the reaction gave a better
bonds of N-sulfonyl aldimines[9a,10b–10d,13a] and C=C result, affording the product in 64% yield, when it was per-
double bonds of methylenemalononitriles,[10a] male- formed at 120 °C in toluene under Ar for 24 h (Entries 21
imides,[13b] and enones,[10e] as well as N=N double bonds and 22).
of azodicarboxylates.[9c] As we can see from the literature
reports,[9–13] the reactivity of 2-alkylazarenes varied with the
Table 1. 2,6-Dimethylpyridine in reaction with benzaldehyde under
different conditions.[a]
structures of the azarenes. Generally speaking, 2,6-dimeth-
ylpyridine afforded the corresponding products in better
yields than 2-methylpyridine, whereas the reactivity of 2-
methylquinolines was somewhat different from that of the
2-methylpyridines. For example, different catalysts were
Entry
Catalyst
Solvent
Yield [%][b]
needed when 2-methylpyridine and 2-methylquinoline re-
acted with azodicarboxylates,[9c] and different products
were obtained in the case of reaction with isatin.[11a] On
the other hand, in the addition of 2-alkylazaarenes to C=O
double bonds, either the electrophilic reagents were limited
to the active isatins[11a,12a] and ethyl glyoxylate[10f,10g] or the
2-alkylazaarenes were limited to 2-methylquinolines.[11b,14]
The synthesis of 1-phenyl-2-(pyridin-2-yl)ethanol through a
reaction between 2-methylpyridine and benzaldehyde cata-
lyzed by a Lewis acid, for instance, was not even included
in the reported case.[10f] It was formed through the reaction
1
2
3
4
5
6
7
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
K2CO3
NaHSO4
MgSO4
AlCl3
FeCl3
LiCl
toluene
DMF
1,4-dioxane
THF
CHCl3
DCE
EtOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
37
0
trace
29
31
32
trace
trace
trace
0
13
17
8[c]
9[c]
10[c]
11[c]
12[c]
between benzaldehyde and 2-methylpyridyl anion generated 13[c]
15
13
31
25
14[c]
15
16
17
18
ZnCl2
with nBuLi.[15] To the best of our knowledge, no extensive
research into reactions between 2-methylazaarenes and
common aldehydes has been reported. Therefore, to investi-
gate the reactivity of different 2-alkylazaarenes and reac-
tions between 2-methylazaarenes and aldehydes, and also in
conjunction with our continuing efforts in research into
Lewis-acid-catalyzed synthesis of nitrogen heterocycles,[16]
we would like to report our investigation into reactions be-
tween 2-methylazaarenes and common aldehydes catalyzed
by different Lewis acids, which were optimized on the basis
of the structures of the 2-methylazaarenes.
Dy(OTf)3
Yb(OTf)3
La(OTf)3
La(Pfb)3
Sc(Pfb)3
LiNTf2
LiNTf2
LiNTf2
35
trace
trace
52
40
64
19
20[c]
21[c][d]
22[c][e]
[a] Reaction conditions: 1a (0.6 mmol), 2a (0.3 mmol), catalyst
(5 mol-%), solvent (0.5 mL), 90 °C, Ar, 24 h. [b] Isolated yields.
[c] The catalyst loading was 10 mol-%. [d] The reaction was con-
ducted in air. [e] The reaction temperature was 120 °C.
With the optimized conditions to hand, a variety of alde-
hydes with electronically varied aromatic and heteroarom-
Results and Discussion
Initially, 2,6-dimethylpyridine (1a) and benzaldehyde (2a) atic substituents, as well as aliphatic aldehydes, were exam-
were employed as substrates for pursuing the optimal con- ined. The reaction was found to be sensitive to the elec-
ditions for this reaction (Table 1). To our delight, in the tronic substituents (Table 2). Arylaldehydes substituted
preliminary trials with 5 mol-% of Sc(OTf)3 as catalyst, the with electron-withdrawing groups such as trifluoromethyl,
desired reaction proceeded readily at 90 °C in toluene under cyano, nitro, and halogen reacted smoothly with 2,6-di-
Ar to give the addition product 3aa in 37% yield (Entry 1). methylpyridine (1a), giving the corresponding products in
Further screening with solvents such as DMF, 1,4-dioxane, good to excellent yields (Entries 2–10). Electron-rich alde-
THF, CHCl3, DCE, and EtOH proved to be unsuccessful hydes such as 3- or 4-methyl- or 4-methoxybenzaldehyde
2
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Benzylic Reactions of 2-Methylazaarenes
provided products in somewhat reduced yields (Entries 11– was isolated in only 14% yield (Entry 2). FeCl3 (Entry 3)
13). A heteroaromatic aldehyde such as furan-2-carbal- and rare earth triflates including Sc, Y, and La (Entries 4–
dehyde was also compatible with the system, though only a 6), as well as lanthanum perfluorooctanoate (Entry 7),
moderate yield was observed (Entry 14). Aliphatic alde- showed catalytic activity similar to that of LiNTf2 for this
hydes proved to be less effective than the aromatic ones, reaction. To our delight, though, the yield of 4ca was in-
and relatively low yields were obtained (Entries 15 and 16). creased to 65% when Sc(Pfb)3 was employed (Entry 8). The
Similar results were obtained in the case of 2-methylpyr- result inspired us to apply other RE(Pfb)3 compounds in
idine (1b, Entries 17–26). It was noteworthy that, in accord- this reaction. Of the tested rare earth pentafluorobenzoates,
ance with reactions with other electrophiles,[9–13] 2,6-di- the cheapest – La(Pfb)3 – afforded product 4ca in the high-
methylpyridine (1a) showed higher reactivity than 2-methyl- est yield (89%, Entries 8–11). Amazingly, when the reaction
pyridine (1b) in reacting with aldehydes and gave the corre- was conducted in air, a comparable yield of the product was
sponding products in relatively higher yields.
obtained (Entry 12).
Table 2. 2-Methylpyridines in reactions with different aldehydes.[a]
Table 3. 2-Methylquinoline in reaction with benzaldehyde catalyzed
by different Lewis acids.[a]
Entry
R
RЈ
Product
Yield [%][b]
Entry
Cat.
Yield [%][b]
1
2
3
4
5
6
7
8
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
H
H
H
H
H
H
H
H
H
C6H5
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
64
92
89
93
98
91
76
80
82
84
54
63
42
56
32
20
57
83
80
92
69
78
40
46
40
48
1[c]
2[c]
3[c]
4
5
6
7
8
9
LiNTf2
Cu(OTf)2
FeCl3
34
14
36
39
38
32
32
65
89
13
86
88
2-CF3-C6H4
4-CN-C6H4
4-NO2-C6H4
3-NO2-C6H4
2-NO2-C6H4
4-Cl-C6H4
2-F-C6H4
3-F-C6H4
4-F-C6H4
3-CH3-C6H4
4-CH3-C6H4
4-CH3O-C6H4
2-C4H3O
Sc(OTf)3
Y(OTf)3
La(OTf)3
La(PFO)3
Sc(Pfb)3
La(Pfb)3
Yb(Pfb)3
Sm(Pfb)3
La(Pfb)3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3aj
3ak
3al
10
11
12[d]
3am
3an
3ao
3ap
3ba
3bb
3bc
3bd
3be
3bf
3bg
3bh
3bi
[a] The reaction was performed by using: 1c (0.36 mmol), 2a
(0.3 mmol), cat. (5 mol-%), toluene (0.5 mL), under Ar, 120 °C for
24 h. [b] Isolated yields. [c] The catalyst loading was 10 mol-%.
[d] The reaction was conducted in air.
Cy
C11H23
C6H5
2-CF3-C6H4
4-CN-C6H4
4-NO2-C6H4
4-Cl-C6H4
3-F-C6H4
3-CH3-C6H4
4-CH3-C6H4
4-CH3O-C6H4
2-C4H3O
The scope of the process with various aldehydes was
studied under the optimized conditions (Table 4). The
transformation proceeded very efficiently with a wide range
of benzaldehydes bearing o-, m-, or p-electron-withdrawing
or -electron-neutral groups on the phenyl ring (Entries 2–
10). Relatively low yields were obtained in the cases of aryl-
aldehydes with electron-donating groups and the aliphatic
and heterocyclic aldehydes (Entries 11–13). Furthermore,
substituted 2-methylquinolines were studied as well: 2-
methyl-8-nitroquinoline reacted with benzaldehyde well to
H
3bj
[a] The reaction was performed by using: 1a or 1b (0.6 mmol), 2
(0.3 mmol), LiNTf2 (0.03 mmol), toluene (0.5 mL), 120 °C for 24 h
under Ar. [b] Isolated yields.
Subsequently, 2-methylquinoline (1c) was employed to give the product 4da in high yield (Entry 14). Notably, 3-
react with aldehydes. However, the expected product was [2-(7-chloroquinolin-2-yl)vinyl]benzaldehyde (4ea), valuable
not detected in the reaction between 2-methylquinoline and for the preparation of many leukotriene receptor antago-
benzaldehyde catalyzed by LiNTf2, and what we obtained nists,[5] was synthesized conveniently through this transfor-
was the dehydrated product (E)-2-styrylquinoline (4ca, the mation with excellent yield (Entry 15). Significantly, in all
E/Z isomerism was determined by comparing the 1H NMR cases, only the E isomers were formed.
spectra of the product with literature reports[10c,13]), in 34%
yield and with only the E isomer being formed.
Inspired by the excellent results above, we suspected that
2-alkenylpyridines, which are ubiquitous structural motifs
Considering the wide application of 2-alkenylquinolines in biologically relevant molecules but could be synthesized
in the synthesis of medical compounds,[5] further modifica- only with difficulty[13a] or in low yields[10c] through the re-
tion of the reaction conditions, especially with regard to the ported direct C(sp3)–H bond functionalization, could be
catalyst, was adopted to improve the yield of 4ca. As out- obtained through reactions between 2-methylpyridines and
lined in Table 3, when Cu(OTf)2 was employed, the product aldehydes in the presence of an appropriate catalyst. As
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D. Mao, G. Hong, S. Wu, X. Liu, J. Yu, L. Wang
Table 5. Access to different 2-alkenylpyridines.[a]
FULL PAPER
Table 4. 2-Methylquinolines in reactions with different aldehydes.[a]
Entry
R
RЈ
Product
Yield [%][b]
Entry
R
RЈ
Product
Yield [%][b]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
8-NO2
7-Cl
C6H5
4ca
4cb
4cc
4cd
4ce
4cf
4cg
4ch
4ci
4cj
4ck
4cl
4cm
4da
4ea
88
97
96
99
99
91
94
93
89
87
55
48
72
90
97
1
2
3
4
5
6
7
8
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
6-CH3
H
H
H
H
H
H
H
H
H
C6H5
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
82
98
90
97
89
80
72
73
55
43
65
77
96
88
90
92
89
87
62
66
54
48
40
62
2-CF3-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-F-C6H4
3-F-C6H4
4-F-C6H4
4-Cl-C6H4
4-CH3-C6H4
2-OH-C6H4
Cy
2-CF3-C6H4
4-CN-C6H4
3-NO2-C6H4
3-F-C6H4
4-F-C6H4
3-CH3-C6H4
4-CH3-C6H4
4-CH3O-C6H4
Cy
9
9
10
11
12
13
14
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4aj
C4H3O
C6H5
4ak
4ba
4bb
4bc
4bd
4be
4bf
4dg
4bh
4bi
2-C4H3O
C6H5
3-CHO-C6H4
2-CF3-C6H4
4-CN-C6H4
2-NO2-C6H4
3-NO2-C6H4
3-F-C6H4
4-F-C6H4
3-CH3-C6H4
4-CH3-C6H4
4-CH3O-C6H4
2-OH-C6H4
Cy
[a] The reaction was performed by using:
(0.3 mmol), La(Pfb)3 (5 mol-%), toluene (0.5 mL), in air, 120 °C for
24 h. [b] Isolated yields.
1
(0.36 mmol), 2
shown in Table 1, Entry 18, due to the low reactivity of 2,6-
dimethylpyridine relative to 2-methylquinoline, only traces
of 3aa and no dehydration product were detected in the
reaction between 2,6-dimethylpyridine (1a) and benzalde-
hyde (2a) in the presence of La(Pfb)3. An attempt to com-
bine La(Pfb)3 and LiNTf2 led to a messy mixture. To our
delight, though, in the presence of LiNTf2 and H2NTf the
expected (E)-2-methyl-6-styrylpyridine (4aa) was obtained
H
H
H
H
4bj
4bk
4bl
C4H3O
4bm
[a] The reaction was performed by using:
(0.3 mmol), LiNTf2 (10 mol-%) and H2NTf (10 mol-%), toluene
(0.5 mL), under Ar, 120 °C for 24 h. [b] Isolated yields.
1
(0.6 mmol), 2
exclusively as the E isomer in 82% yield (Table 5, Entry 1). to excellent yields (4aa–4bm). Substituent effects similar to
The application of the catalyst system LiNTf2 in con- those seen in the synthesis of 2-(pyridin-2-yl)ethanols was
junction with H2NTf was then applied to synthesize a series revealed, including the facts that electron-deficient alde-
of 2-alkenylpyridines (Table 5). Aldehydes with different hydes provided products in higher yields than electron-rich
substituents could react smoothly with 1a and 1b, affording ones and that 2,6-dimethylpyridine (1a) showed higher reac-
exclusively the (E)-2-alkenylpyridine derivatives in moderate tivity than 2-methylpyridine (1b).
Scheme 1. Proposed pathway for the formation of 3 and 4.
4
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Benzylic Reactions of 2-Methylazaarenes
tored by TLC. After 24 h, the solvent was evaporated under re-
duced pressure and the residue was purified by flash column
chromatography on a silica gel to give the desired product 3aa–3bj.
On the basis of the above experimental results and the
literature reports, a plausible reaction pathway is proposed
in Scheme 1. Firstly, the Brønsted acidity of the benzylic
C–H bond of a 2-substituted azaarene is enhanced by coor- 2-(6-Methylpyridin-2-yl)-1-phenylethanol (3aa): Yield 40.9 mg,
64%; yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.51 (t, J =
dination to the Lewis acid. Thus, C–H bond cleavage either
7.6 Hz, 1 H), 7.44–7.42 (m, 2 H), 7.37–7.33 (m, 2 H), 7.28–7.42 (m,
by the counterion of the Lewis acid or by the external base
(azaarene 1) would generate the metal enamide A.[10e] En-
1 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.91 (d, J = 7.6 Hz, 1 H), 6.51 (br.
s, 1 H), 5.14 (dd, J = 4.4, 8.0 Hz, 1 H), 3.13–3.04 (m, 2 H), 2.57
amide A cooperates with aldehyde 2 to form the transition
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.1, 156.3,
state B. Then intermediate C is generated through B. In
143.2, 136.2, 127.2, 126.2, 124.8, 120.2, 119.6, 72.4, 44.3, 23.3 ppm.
the case of 2-methylpyridines reacting with aldehydes in the
presence of LiNTf2 as catalyst, 3aa–3bj (Table 2) were
formed after protonation. In the presence of H2NTf, the
(E)-2-alkenylpyridines 4aa–4bm (Table 5) were obtained
through the elimination of H2O from C. When 2-methyl-
quinolines were employed, the stable (E)-2-alkenylquinol-
ines 4ca–4ea (Table 4) were formed by dehydration, which
was promoted by the thermodynamic stability of the large
conjugation structure of the quinoline.
HRMS (ESI) calcd. for C14H16NO [M + H]+ 214.1232; found
214.1228.
2-(6-Methylpyridin-2-yl)-1-[2-(trifluoromethyl)phenyl]ethanol (3ab):
1
Yield 77.6 mg, 92%; yellow oil. H NMR (400 MHz, CDCl3): δ =
7.94 (d, J = 4.0 Hz, 1 H), 7.64–7.52 (m, 3 H), 7.38 (t, J = 7.6 Hz,
1 H), 7.08 (d, J = 7.6 Hz, 1 H), 6.91 (d, J = 7.6 Hz, 1 H), 6.75 (br.
s, 1 H), 5.50–5.48 (m, 1 H), 3.05–2.95 (m, 2 H), 2.58 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 159.0, 157.4, 143.1, 137.4, 132.2,
128.1, 127.2, 126.5 (d, J = 30.0 Hz), 125.3 (q, J = 5.8 Hz), 121.5,
120.4, 69.2, 45.4, 24.3 ppm. HRMS (ESI) calcd. for C15H15F3NO
[M + H]+ 282.1106; found 282.1104.
Conclusions
4-[1-Hydroxy-2-(6-methylpyridin-2-yl)ethyl]benzonitrile (3ac): Yield
64.3 mg, 90%; yellow solid; m.p. 164–167 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.64–7.62 (m, 2 H), 7.55–7.50 (m, 3 H), 7.06 (d, J =
7.6 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H), 6.17 (br. s, 1 H), 5.19 (dd,
J = 3.2, 8.8 Hz, 1 H), 3.11–2.99 (m, 2 H), 2.56 (s, 3 H) ppm. 13C
Reactions between 2-methylazaarenes and aldehydes in
the presence of different catalysts were investigated exten-
sively. 2-(Pyridin-2-yl)ethanols were afforded, in yields
ranging from 20% to 98%, through LiNTf2-catalyzed benz- NMR (100 MHz, CDCl3): δ = 158.2, 157.4, 149.8, 137.4, 132.1,
126.6, 121.6, 120.8, 119.0, 110.7, 72.6, 44.8, 24.3 ppm. HRMS
ylic reactions between 2-methylpyridines and aldehydes for
the first time. In the presence of La(Pfb)3 as catalyst in air,
2-methylquinolines reacted with aldehydes to furnish the
(ESI) calcd. for C15H15N2O [M + H]+ 239.1184; found 239.1185.
2-(6-Methylpyridin-2-yl)-1-(4-nitrophenyl)ethanol
(3ad):
Yield
corresponding 2-alkenylquinolines exclusively as the E iso- 72.0 mg, 93%; yellow solid; m.p. 127–129 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.20 (d, J = 8.8 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 2 H),
7.53 (t, J = 7.6 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.90 (d, J =
7.6 Hz, 1 H), 5.25 (dd, J = 2.8, 8.8 Hz, 1 H), 3.14–3.01 (m, 2 H),
2.57 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.2, 157.5,
151.7, 147.1, 137.5, 126.6, 123.6, 121.7, 120.6, 72.6, 44.5, 24.3 ppm.
HRMS (ESI) calcd. for C14H15N2O3 [M + H]+ 259.1083; found
259.1084.
mers in moderate to excellent yields. Furthermore, 2-alken-
ylpyridines, relatively hard to obtain by direct C(sp3)–H
bond functionalization, were afforded exclusively as the E
isomers through reactions between 2-methylpyridines and
aldehydes catalyzed by LiNTf2 in conjunction with H2NTf.
All of these azaarene derivatives were important precursors
or intermediates of many natural products and medical
compounds.
2-(6-Methylpyridin-2-yl)-1-(3-nitrophenyl)ethanol
(3ae):
Yield
75.9 mg, 98%; yellow solid; m.p. 110–113 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.29 (s, 1 H), 8.11–8.09 (m, 1 H), 7.77 (d, J = 7.6 Hz,
1 H), 7.53–7.50 (m, 2 H), 7.07 (d, J = 8.0 Hz, 1 H), 6.92 (d, J =
7.6 Hz, 1 H), 6.86 (br. s, 1 H), 5.23 (dd, J = 3.2, 8.4 Hz, 1 H), 3.14–
3.03 (m, 2 H), 2.56 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 158.0, 157.4, 148.2, 146.3, 137.5, 132.6, 132.1, 129.2, 122.2, 121.7,
120.9, 72.5, 44.7, 24.2 ppm. HRMS (ESI) calcd. for C14H15N2O3
[M + H]+ 259.1083; found 259.1082.
Experimental Section
General: Where necessary, non-aqueous reactions and manipula-
tions were performed under argon with use of standard Schlenk
techniques. All solvents were dried and degassed by standard meth-
ods before use and stored under argon. Reagents were purchased
and used without further purification. Column chromatography
was performed with silica gel (200–300 mesh ASTM). Melting
points were uncorrected. 1H NMR and 13C NMR spectra were
recorded at 400 MHz and 100 MHz, respectively, with use of tet-
ramethylsilane as an internal reference. 1H NMR assignment ab-
breviations are as follows: singlet (s), doublet (d), triplet (t), quartet
(q), broad singlet (br. s), doublet of doublets (dd), doublet of trip-
lets (dt), and multiplet (m). High-resolution mass spectrometry
(HRMS) was performed with an ESI-TOF spectrometer.
2-(6-Methylpyridin-2-yl)-1-(2-nitrophenyl)ethanol
(3af):
Yield
70.5 mg, 91%; yellow solid; m.p. 104–106 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.96 (dd, J = 7.6, 12.0 Hz, 2 H), 7.64 (t, J = 7.6 Hz,
1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.07 (d,
J = 7.6 Hz, 1 H), 6.99 (d, J = 7.6 Hz, 1 H), 5.62 (d, J = 8.8 Hz, 1
H), 3.29 (dd, J = 1.6, 14.8 Hz, 2 H), 3.03–2.97 (m, 1 H), 2.57 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.6, 157.3, 147.5,
139.7, 137.6, 133.5, 128.6, 127.9, 124.2, 121.6, 120.7, 69.2, 44.2,
24.3 ppm. HRMS (ESI) calcd. for C14H15N2O3 [M + H]+ 259.1083;
found 259.1085.
General Procedure for the Synthesis of 2-(Pyridin-2-yl)ethanols 3aa–
3bj: Under argon, LiNTf2 (8.6 mg, 10 mol-%), 2,6-dimethylpyridine
(1a, 0.6 mmol) or 2-methylpyridine (1b, 0.6 mmol), an aldehyde 2
(0.3 mmol), and dry toluene (0.5 mL) were placed in a dried
Schlenk tube. The mixture was kept stirring at 120 °C and moni-
1-(4-Chlorophenyl)-2-(6-methylpyridin-2-yl)ethanol (3ag): Yield
1
56.5 mg, 76%; yellow oil. H NMR (400 MHz, CDCl3): δ = 7.51
(t, J = 7.6 Hz, 1 H), 7.36–7.34 (m, 2 H), 7.29–7.26 (m, 2 H), 7.04
(d, J = 8.0 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H), 6.51 (br. s, 1 H),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O40073
/KAP1
Date: 26-03-14 17:01:41
Pages: 12
D. Mao, G. Hong, S. Wu, X. Liu, J. Yu, L. Wang
FULL PAPER
5.10 (t, J = 6.0 Hz, 1 H), 3.03 (d, J = 6.0 Hz, 2 H), 2.55 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.7, 157.4, 142.6,
137.3, 132.8, 128.4, 127.2, 121.5, 120.7, 72.8, 45.1, 24.3 ppm.
HRMS (ESI) calcd. for C14H15ClNO [M + H]+ 248.0842; found
248.0840.
1-(Furan-2-yl)-2-(6-methylpyridin-2-yl)ethanol (3an): Yield 34.1 mg,
56%; yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.52 (t, J =
7.6 Hz, 1 H), 7.37 (d, J = 1.2 Hz, 1 H), 7.03 (d, J = 7.6 Hz, 1 H),
6.95 (d, J = 7.6 Hz, 1 H), 6.31 (dd, J = 2.0, 3.2 Hz, 1 H), 6.23 (d,
J = 3.2 Hz, 1 H), 5.17 (dd, J = 3.2, 8.4 Hz, 1 H), 3.29–3.16 (m, 2
H), 2.53 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.6,
157.4, 156.4, 141.6, 137.2, 121.4, 120.7, 110.1, 105.7, 67.4, 41.4,
24.3 ppm. HRMS (ESI) calcd. for C12H14NO2 [M + H]+ 204.1025;
found 204.1027.
1-(2-Fluorophenyl)-2-(6-methylpyridin-2-yl)ethanol (3ah): Yield
1
55.5 mg, 80%; yellow oil. H NMR (400 MHz, CDCl3): δ = 7.61–
7.57 (m, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.23–7.20 (m, 1 H), 7.13
(t, J = 7.6 Hz, 1 H), 7.05–6.99 (m, 2 H), 6.91 (d, J = 7.6 Hz, 1 H),
5.44 (dd, J = 2.4, J = 8.8 Hz, 1 H), 3.18–3.14 (m, 1 H), 3.08–3.02
(m, 1 H), 2.56 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
159.5 (d, J = 243.6 Hz), 159.0, 157.3, 137.3, 131.2 (d, J = 12.9 Hz),
138.4 (d, J = 8.1 Hz), 127.5 (d, J = 4.4 Hz), 124.1 (d, J = 3.5 Hz),
1-Cyclohexyl-2-(6-methylpyridin-2-yl)ethanol (3ao): Yield 21.0 mg,
32%; yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.50 (t, J =
7.6 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.93 (d, J = 7.6 Hz, 1 H),
5.73 (br. s, 1 H), 3.77–3.72 (m, 1 H), 2.89–2.77 (m, 2 H), 2.51 (s, 3
121.4, 120.6, 114.9 (d, J = 21.3 Hz), 67.3, 43.6, 24.4 ppm. HRMS H), 2.06–1.58 (m, 11 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
(ESI) calcd. for C14H15 FNO [M + H]+ 232.1138; found 232.1138. 159.2, 156.3, 136.0, 119.9, 119.5, 74.2, 42.6, 38.9, 28.0, 27.4, 25.6,
25.3, 25.3, 23.3 ppm. HRMS (ESI) calcd. for C14H22NO [M +
1-(3-Fluorophenyl)-2-(6-methylpyridin-2-yl)ethanol (3ai): Yield
56.9 mg, 82%; yellow oil. H NMR (400 MHz, CDCl3): δ = 7.50
H]+ 220.1701; found 220.1702.
1
(t, J = 7.6 Hz, 1 H), 7.27–7.25 (m, 1 H), 7.17–7.13 (m, 2 H), 7.03
(d, J = 7.6 Hz, 1 H), 6.95–6.88 (m, 2 H), 6.54 (br. s, 1 H), 5.13–
5.10 (m, 1 H), 3.05–3.03 (m, 2 H), 2.54 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 162.9 (d, J = 243.6 Hz), 158.7, 157.4, 146.9
(d, J = 6.9 Hz), 137.3, 129.7 (d, J = 8.0 Hz), 121.4, 120.7, 114.1,
112.9, 112.7, 72.8, 45.0, 24.3 ppm. HRMS (ESI) calcd. for
C14H15FNO [M + H]+ 232.1138; found 232.1139.
1-(6-Methylpyridin-2-yl)tridecan-2-ol (3ap): Yield 17.5 mg, 20%;
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.50 (t, J = 7.6 Hz, 1
H), 7.01 (d, J = 7.6 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 5.70 (br.
s, 1 H), 4.03–3.97 (m, 1 H), 2.89–2.75 (m, 2 H), 2.51 (s, 3 H), 1.33–
1.26 (m, 23 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.8,
156.3, 136.0, 119.9, 119.4, 70.0, 41.9, 36.2, 30.9, 28.7, 28.6, 28.3,
24.6, 23.3, 21.7, 13.1 ppm. HRMS (ESI) calcd. for C19H34NO [M
+ H]+ 292.2640; found 292.2641.
1-(4-Fluorophenyl)-2-(6-methylpyridin-2-yl)ethanol (3aj): Yield
1
58.3 mg, 84%; yellow oil. H NMR (400 MHz, CDCl3): δ = 7.40
1-Phenyl-2-(pyridin-2-yl)ethanol (3ba): Yield 34.1 mg, 57%; yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 4.8 Hz, 1 H),
7.62 (dt, J = 1.6, 7.6 Hz, 1 H), 7.44–7.42 (m, 2 H), 7.35 (t, J =
7.6 Hz, 2 H), 7.28–7.23 (m, 1 H), 7.20–7.17 (m, 1 H), 7.11 (d, J =
7.6 Hz, 1 H), 5.72 (br. s, 1 H), 5.17 (dd, J = 4.0, 8.4 Hz, 1 H), 3.19–
3.08 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.7, 148.6,
144.1, 136.9, 129.1, 128.4, 128.3, 127.3, 125.9, 125.3, 123.9, 121.8,
73.4, 45.8 ppm. HRMS (ESI) calcd. for C13H14NO [M + H]+
200.1075; found 200.1077.
(t, J = 7.6 Hz, 1 H), 7.28–7.24 (m, 1 H), 7.20–7.16 (m, 2 H), 6.88
(d, J = 2.8 Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 6.32 (br. s, 1 H),
4.98 (dd, J = 4.0, 8.4 Hz, 1 H), 2.98–2.88 (m, 2 H), 2.43 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.1 (dd, J = 15.8,
243.3 Hz), 158.7, 157.4, 136.8 (dd, J = 3.1, 297.3 Hz) 137.3, 128.6
(d, J = 8.0 Hz), 127.5 (d, J = 8.0 Hz), 115.3, 114.9, 72.9, 45.3,
24.3 ppm. HRMS (ESI) calcd. for C14H15FNO [M + H]+ 232.1138;
found 232.1135.
2-(6-Methylpyridin-2-yl)-1-(m-tolyl)ethanol (3ak): Yield 36.8 mg,
54%; yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.50 (t, J =
7.6 Hz, 1 H), 7.27 (s, 1 H), 7.25–7.20 (m, 2 H), 7.10–7.07 (m, 1 H),
2-(Pyridin-2-yl)-1-[2-(trifluoromethyl)phenyl]ethanol (3bb): Yield
66.5 mg, 83%; yellow oil. H NMR (400 MHz, CDCl3): δ = 8.55
(d, J = 4.4 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.67–7.63 (m, 2 H),
1
7.03 (d, J = 7.6 Hz, 1 H), 6.91 (d, J = 7.6 Hz, 1 H), 6.31 (br. s, 1 7.59 (t, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.22 (dd, J =
H), 5.09 (dd, J = 3.2, 8.8 Hz, 1 H), 3.11–3.00 (m, 2 H), 2.55 (s, 3
H), 2.36 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.3,
157.4, 144.2, 137.9, 137.2, 128.2, 128.0, 126.7, 122.9, 121.3, 120.6,
73.4, 45.4, 24.4, 21.5 ppm. HRMS (ESI) calcd. for C15H18NO [M
+ H]+ 228.1388; found 228.1389.
5.2, 7.6 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H), 6.22 (br. s, 1 H), 5.52
(dt, J = 2.0, 7.6 Hz, 1 H), 3.11–3.01 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.6, 148.6, 143.0, 137.2, 132.2, 128.0,
127.3, 125.4 (q, J = 5.8 Hz), 123.6, 122.0, 69.1 (d, J = 2.1 Hz),
45.7 ppm. HRMS (ESI) calcd. for C14H13F3NO [M
268.0949; found 268.0950.
+
H]+
2-(6-Methylpyridin-2-yl)-1-(p-tolyl)ethanol (3al): Yield 42.9 mg,
63%; yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.50 (t, J =
7.6 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 80%; yellow solid; m.p. 130–132 °C. H NMR (400 MHz, CDCl3):
7.03 (d, J = 7.6 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 6.26 (br. s, 1 δ = 8.53 (d, J = 4.8 Hz, 1 H), 7.66–7.62 (m, 3 H), 7.54–7.52 (m, 2
4-[1-Hydroxy-2-(pyridin-2-yl)ethyl]benzonitrile (3bc): Yield 53.8 mg,
1
H), 5.09 (dd, J = 3.6, 8.8 Hz, 1 H), 3.11–3.00 (m, 2 H), 2.55 (s, 3
H), 2.34 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2,
157.4, 141.3, 137.2, 136.8, 129.0, 125.8, 121.3, 120.7, 73.3, 45.5,
24.4, 21.2 ppm. HRMS (ESI) calcd. for C15H18NO [M + H]+
228.1388; found 228.1387.
H), 7.22 (dd, J = 1.2, 7.2 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 1 H), 7.23
(dd, J = 3.2, 8.4 Hz, 1 H), 4.01 (br. s, 1 H), 3.17–3.05 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.9, 149.5, 148.5, 137.2, 132.2,
126.6, 123.9, 122.1, 119.0, 72.6, 45.0 ppm. HRMS (ESI) calcd. for
C14H13F3NO [M + H]+ 225.1028; found 225.1030.
1-(4-Methoxyphenyl)-2-(6-methylpyridin-2-yl)ethanol (3am): Yield
30.6 mg, 42%; yellow solid; m.p. 109–111 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.50 (t, J = 8.0 Hz, 1 H), 7.36–7.34 (m, 2 H), 7.03 (d,
1-(4-Nitrophenyl)-2-(pyridin-2-yl)ethanol (3bd): Yield 67.4 mg, 92%;
yellow solid; m.p. 65–68 °C. 1H NMR (400 MHz, CDCl3): δ = 8.53
(d, J = 4.4 Hz, 1 H), 8.20 (d, J = 8.8 Hz, 2 H), 7.65 (dt, J = 1.6,
J = 8.0 Hz, 1 H), 6.91–6.87 (m, 3 H), 6.05 (br. s, 1 H), 5.07 (dd, J 7.6 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 2 H), 7.22 (dd, J = 1.2, 7.6 Hz,
= 3.2, 9.2 Hz, 1 H), 3.80 (s, 3 H), 3.11–3.00 (m, 2 H), 2.56 (s, 3 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.35 (br. s, 1 H), 5.29 (dd, J = 3.2,
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.1, 157.7, 156.2,
136.1, 135.4, 126.0, 120.2, 119.6, 112.6, 71.9, 54.1, 44.5, 23.3 ppm.
HRMS (ESI) calcd. for C15H18NO2 [M + H]+ 244.1388; found
244.1387.
8.8 Hz, 1 H), 3.19–3.07 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.8, 151.5, 148.5, 137.2, 126.6, 123.8, 123.6, 122.1,
72.5, 44.8 ppm. HRMS (ESI) calcd. for C13H13N2O3 [M + H]+
245.0926; found 245.0925.
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O40073
/KAP1
Date: 26-03-14 17:01:41
Pages: 12
Benzylic Reactions of 2-Methylazaarenes
1-(4-Chlorophenyl)-2-(pyridin-2-yl)ethanol (3be): Yield 48.4 mg,
1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.72–
7.63 (m, 5 H), 7.51–7.47 (m, 1 H), 7.43–7.38 (m, 3 H), 7.34–7.30
1
69%; yellow oil. H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H),
7.61 (t, J = 7.6 Hz, 1 H), 7.35–7.28 (m, 4 H), 7.18 (t, J = 6.0 Hz, (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.0, 148.3,
1 H), 7.08 (d, J = 7.6 Hz, 1 H), 5.89 (br. s, 1 H), 5.13 (t, J = 6.0 Hz,
136.5, 136.4, 134.4, 129.8, 129.2, 129.0, 128.8, 128.7, 127.6, 127.4,
1 H), 3.13–3.05 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 127.3, 126.2, 119.3 ppm. HRMS (ESI) calcd. for C17H14N
159.4, 148.5, 142.6, 137.0, 132.8, 128.4, 127.2, 123.9, 121.9, 72.7,
[M + H]+ 232.1126; found 232.1128.
45.5 ppm. HRMS (ESI) calcd. for C13H13ClNO [M
234.0686; found 234.0687.
+
H]+
(E)-2-[2-(Trifluoromethyl)styryl]quinoline (4cb): Yield 88.0 mg,
1
98%; yellow solid; m.p. 91–93 °C. H NMR (400 MHz, CDCl3): δ
= 8.18 (d, J = 8.8 Hz, 1 H), 8.10 (d, J = 8.8 Hz, 1 H), 7.98 (dd, J
= 2.0, 16.0 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.82 (d, J = 8.0 Hz,
1 H), 7.77–7.71 (m, 3 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.53 (t, J =
7.6 Hz, 1 H), 7.45–7.40 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 155.6, 148.2, 136.5, 135.6, 133.4, 132.0, 129.9 (d, J
= 1.8 Hz), 129.8, 129.4, 128.1, 127.5, 127.4, 126.6, 126.1, 126.0,
118.8 ppm. HRMS (ESI) calcd. for C18H13F3N [M + H]+ 300.1000;
found 300.1001.
1-(3-Fluorophenyl)-2-(pyridin-2-yl)ethanol (3bf): Yield 50.8 mg,
78%; yellow oil. H NMR (400 MHz, CDCl3): δ = 8.49–8.48 (m,
1
1 H), 7.63–7.59 (m, 1 H), 7.31–7.25 (m, 1 H), 7.19–7.13 (m, 3 H),
7.09 (d, J = 7.6 Hz, 1 H), 6.93 (t, J = 8.4 Hz, 1 H), 6.01 (br. s, 1 H),
5.16–5.13 (m, 1 H), 3.13–3.05 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.7 (t, J = 241.6 Hz), 148.5, 137.0, 129.8 (d, J =
8.1 Hz), 123.9 (d, J = 1.3 Hz), 121.9, 121.4 (d, J = 2.6 Hz), 114.0
(d, J = 21.1 Hz), 112.8 (d, J = 21.8 Hz), 72.7, 45.4 (J =
5.0 Hz) ppm. HRMS (ESI) calcd. for C13H13FNO [M + H]+
218.0981; found 218.0980.
(E)-2-(2-Nitrostyryl)quinoline (4cc): Yield 79.6 mg, 96%; yellow so-
lid; m.p. 99–101 °C. 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J =
8.8 Hz, 1 H), 8.11 (d, J = 8.4 Hz, 1 H), 8.08 (s, 1 H), 8.02 (d, J =
8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H),
7.77–7.71 (m, 2 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.54 (t, J = 7.6 Hz,
1 H), 7.50–7.46 (m, 1 H), 7.41 (d, J = 16.4 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 154.1, 147.1, 135.6, 133.1, 132.3,
131.2, 128.9, 128.3, 128.1, 127.8, 127.4, 126.5, 125.6, 123.8,
117.9 ppm. HRMS (ESI) calcd. for C17H13N2O2 [M + H]+
277.0977; found 277.0976.
2-(Pyridin-2-yl)-1-(m-tolyl)ethanol (3bg): Yield 25.6 mg, 40%; yel-
1
low oil. H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 4.0 Hz, 1
H), 7.62 (dt, J = 2.0, 7.6 Hz, 1 H), 7.27 (s, 1 H), 7.24–7.17 (m, 3
H), 7.13–7.07 (m, 2 H), 5.67 (br. s, 1 H), 5.13 (dd, J = 3.6, 8.8 Hz,
1 H), 3.18–3.06 (m, 2 H), 2.36 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.9, 148.6, 144.0, 138.0, 136.9, 128.2, 128.1, 126.6,
123.8, 122.9, 121.7, 73.4, 45.7, 21.5 ppm. HRMS (ESI) calcd. for
C14H16NO [M + H]+ 214.1232; found 214.1230.
(E)-2-(3-Nitrostyryl)quinoline (4cd): Yield 82.0 mg, 99%; yellow so-
lid; m.p. 161–163 °C. H NMR (400 MHz, CDCl3): δ = 8.51 (s, 1
2-(Pyridin-2-yl)-1-(p-tolyl)ethanol (3bh): Yield 29.4 mg, 46%; yel-
low oil. H NMR (400 MHz, CDCl3): δ = 8.53 (d, J = 4.4 Hz, 1
1
1
H); 8.20–8.16 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.94 (d, J =
7.6 Hz, 1 H), 7.83–7.80 (m, 3 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.60–
7.50 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.8, 148.7,
148.2, 138.4, 136.7, 132.9, 131.8, 131.6, 130.0, 129.8, 129.3, 127.6,
126.7, 123.0, 121.7, 119.7 ppm. HRMS (ESI) calcd. for
C17H13N2O2 [M + H]+ 277.0977; found 277.0976.
H), 7.62 (dt, J = 2.0, 7.6 Hz, 1 H), 7.33–7.31 (m, 2 H), 7.20–7.10
(m, 4 H), 5.58 (br. s, 1 H), 5.13 (dd, J = 3.2, 8.8 Hz, 1 H), 3.18–
3.06 (m, 2 H), 2.34 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 159.8, 148.6, 141.1, 136.9, 129.0, 125.8, 123.8, 121.7, 73.2, 45.8,
21.1 ppm. HRMS (ESI) calcd. for C14H16NO [M + H]+ 214.1232;
found 214.1230.
(E)-2-(4-Nitrostyryl)quinoline (4ce): Yield 82.0 mg, 99%; yellow so-
lid; m.p. 171–173 °C. H NMR (400 MHz, CDCl3): δ = 8.26 (d, J
1-(4-Methoxyphenyl)-2-(pyridin-2-yl)ethanol (3bi): Yield 27.5 mg,
40%; yellow solid; m.p. 102–103 °C. H NMR (400 MHz, CDCl3):
1
1
= 8.8 Hz, 2 H), 8.19 (d, J = 8.8 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1
H), 7.82 (d, J = 8.4 Hz, 1 H), 7.79–7.73 (m, 4 H), 7.67 (d, J =
8.4 Hz, 1 H), 7.57–7.51 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.6, 147.2, 146.3, 141.9, 135.7, 132.1, 130.6, 129.0,
128.3, 126.6, 126.5, 125.8, 123.1, 118.7 ppm. HRMS (ESI) calcd.
for C17H13N2O2 [M + H]+ 277.0977; found 277.0979.
δ = 8.53 (d, J = 4.4 Hz, 1 H), 7.62 (dt, J = 1.6, 7.6 Hz, 1 H), 7.35–
7.33 (m, 2 H), 7.18 (dd, J = 1.6, 7.2 Hz, 1 H), 7.11 (d, J = 8.0 Hz,
1 H), 6.89–6.87 (m, 2 H), 6.12 (dd, J = 3.2, 8.8 Hz, 1 H), 5.35 (br.
s, 1 H), 3.80 (s, 3 H), 3.18–3.06 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.8, 158.8, 148.6, 136.9, 136.3, 127.1, 123.9, 121.7,
113.7, 73.0, 55.3, 45.8 ppm. HRMS (ESI) calcd. for C14H16NO2 [M
+ H]+ 230.1181; found 230.1180.
(E)-2-(2-Fluorostyryl)quinoline (4cf): Yield 68.0 mg, 91%; yellow
1
solid; m.p. 79–81 °C. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J
1-(Furan-2-yl)-2-(pyridin-2-yl)ethanol (3bj): Yield 27.2 mg, 48%;
= 8.4 Hz, 1 H), 8.80 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1
H), 7.73–7.69 (m, 1 H), 7.67–7.62 (m, 2 H), 7.50 (t, J = 7.6 Hz, 1
H), 7.40–7.32 (m, 4 H), 7.04–6.99 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 161.0, 158.5, 154.8, 147.2, 135.3, 130.1 (d,
J = 4.8 Hz), 128.8 (d, J = 8.3 Hz), 128.7, 128.2, 126.6 (d, J =
3.1 Hz), 126.5, 126.4, 125.5 (d, J = 3.8 Hz), 125.3, 123.4 123.3 (d,
J = 3.4 Hz), 118.1 ppm. HRMS (ESI) calcd. for C17H13FN [M +
H]+ 250.1032; found 250.1030.
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 8.49 (d, J = 4.4 Hz,
1 H), 7.62 (dt, J = 2.0, 7.6 Hz, 1 H), 7.37–7.36 (m, 1 H), 7.19–7.13
(m, 2 H), 6.31–6.30 (m, 1 H), 6.23–6.22 (m, 1 H), 5.20 (dd, J = 3.6,
8.4 Hz, 1 H), 4.39 (br. s, 1 H), 3.34–3.26 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.2, 155.2, 147.5, 140.7, 135.9, 122.8,
120.7, 109.1, 104.8, 66.2, 40.8 ppm. HRMS (ESI) calcd. for
C11H12NO2 [M + H]+ 190.0868; found 190.0870.
General Procedure for the Synthesis of 2-Alkenyl Quinolines 4ca–
4ea: In air, La(Pfb)3 (11.6 mg, 5 mol-%), 2-methylquinoline (1c,
0.36 mmol) or 1d or 1e (0.36 mmol), an aldehyde 2 (0.3 mmol), and
toluene (0.5 mL) were placed in a tube. The mixture was kept stir-
ring at 120 °C and monitored by TLC. After 24 h the solvent was
evaporated under reduced pressure and the residue was purified by
flash column chromatography on silica gel to give the desired prod-
uct 4ca–4ea.
(E)-2-(3-Fluorostyryl)quinoline (4cg): Yield 70.3 mg, 94%; yellow
solid; m.p. 80–82 °C. H NMR (400 MHz, CDCl3): δ = 8.13 (d, J
1
= 8.8 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 1 H),7.84 (d, J = 16.4 Hz, 1
H), 7.78 (d, J = 8.4 Hz, 1 H), 7.76–7.69 (m, 3 H), 7.52–7.46 (m, 2
H), 7.32–7.26 (m, 1 H), 7.18 (t, J = 7.6 Hz, 1 H), 7.13–7.09 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.2 (d, J = 244.2 Hz),
155.4, 148.2, 138.9 (d, J = 7.6 Hz), 136.5, 133.1 (d, J = 2.8 Hz),
130.3, 130.2, 129.9, 129.3, 127.6, 127.4, 126.4, 123.2 (d, J = 2.7 Hz),
119.4, 115.4 (d, J = 21.2 Hz), 113.5 (d, J = 21.7 Hz) ppm. HRMS
(ESI) calcd. for C17H13FN [M + H]+ 250.1032; found 250.1030.
(E)-2-Styrylquinoline (4ca): Yield 61.1 mg, 88%; yellow solid; m.p.
1
98–100 °C. H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 8.4 Hz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O40073
/KAP1
Date: 26-03-14 17:01:41
Pages: 12
D. Mao, G. Hong, S. Wu, X. Liu, J. Yu, L. Wang
FULL PAPER
(E)-2-(3-Fluorostyryl)quinoline (4ch): Yield 69.6 mg, 93%; yellow
solid; m.p. 123–125 °C. H NMR (400 MHz, CDCl3): δ = 8.06 (d,
127.8, 127.6, 124.4, 123.8, 121.5 ppm. HRMS (ESI) calcd. for
C17H13N2O2 [M + H]+ 277.0977; found 277.0978.
1
J = 8.4 Hz, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1
H), 7.66–7.62 (m, 1 H), 7.50 (d, J = 6.0 Hz, 1 H), 7.57–7.52 (m, 3
H), 7.43 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 15.2 Hz, 1 H), 7.02 (t, J
= 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.9 (d,
J = 247.3 Hz), 155.8, 148.2, 136.4, 133.2, 132.7 (d, J = 3.2 Hz),
129.8, 129.2, 128.9 (d, J = 8.2 Hz), 128.7 (d, J = 2.3 Hz), 127.5,
127.4, 126.2, 119.3, 115.8 (d, J = 21.5 Hz) ppm. HRMS (ESI)
calcd. for C17H13FN [M + H]+ 250.1032; found 250.1031.
(E)-3-[2-(7-Chloroquinolin-2-yl)vinyl]benzaldehyde (4ea): Yield
85.5 mg, 97%; yellow solid; m.p. 123–125 °C. 1H NMR (400 MHz,
CDCl3): δ = 10.08 (s, 1 H), 8.14–8.12 (m, 2 H), 8.09 (d, J = 1.6 Hz,
1 H), 7.89 (d, J = 7.6 Hz, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.79 (d,
J = 11.2 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.64 (d, J = 8.8 Hz,
1 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.48–7.43 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 192.1, 156.2, 148.6, 137.4, 136.9, 136.4,
135.7, 133.4, 133.0, 130.1, 129.8, 129.6, 128.7, 128.3, 128.2, 127.4,
125.8, 119.9 ppm. HRMS (ESI) calcd. for C17H18ClNO [M + H]+
294.0686; found 294.0688.
(E)-2-(4-Chlorostyryl)quinoline (4ci): Yield 71.0 mg, 89%; yellow
1
solid; m.p. 140–142 °C. H NMR (400 MHz, CDCl3): δ = 8.12 (d,
J = 8.4 Hz, 1 H), 8.07 (d, J = 8.8 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1
H), 7.71 (t, J = 7.6 Hz, 1 H), 7.65 (d, J = 4.8 Hz, 1 H), 7.62 (d, J
= 2.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.50 (t, J = 7.6 Hz, 1 H),
7.38–7.34 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.5,
147.2, 135.4, 134.0, 133.2, 131.9, 128.8, 128.4, 128.2, 128.0, 127.3,
126.5, 126.3, 125.3, 118.3 ppm. HRMS (ESI) calcd. for C17H13ClN
[M + H]+ 266.0737; found 266.0736.
General Procedure for the Synthesis of 2-Alkenylpyridines 4aa-4bm:
Under argon, LiNTf2 (8.6 mg, 10 mol-%), H2NTf (4.5 mg, 10 mol-
%), 2,6-dimethylpyridine (1a, 0.6 mmol) or 2-methylpyridine (1b,
0.6 mmol), an aldehyde 2 (0.3 mmol), and dry toluene (0.5 mL)
were placed in a dried Schlenk tube. The mixture was kept stirring
at 120 °C and monitored by TLC. After 24 h, the solvent was evap-
orated under reduced pressure and the residue was purified by flash
column chromatography on a silica gel to give the desired product
4aa–4bm.
(E)-2-(4-Methylstyryl)quinoline (4cj): Yield 64.0 mg, 87%; yellow
1
solid; m.p. 132–134 °C. H NMR (400 MHz, CDCl3): δ = 8.04 (d,
J = 8.4 Hz, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1
H), 7.65–7.60 (m, 2 H), 7.57 (d, J = 6.8 Hz, 1 H), 7.48 (s, 1 H),
7.46 (s, 1 H), 7.43–7.39 (m, 1 H), 7.29 (d, J = 16.4 Hz, 1 H), 7.15
(s, 1 H), 7.13 (s, 1 H), 2.31 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 155.1, 147.2, 137.6, 135.2, 133.3, 132.6, 128.6, 128.4,
128.0, 126.9, 126.4, 126.2, 126.1, 125.0, 118.1, 20.3 ppm. HRMS
(ESI) calcd. for C17H14NO [M + H]+ 246.1283; found 246.1281.
(E)-2-Methyl-6-styrylpyridine (4aa): Yield 50.6 mg, 82%; yellow so-
lid; m.p. 88–90 °C. 1H NMR (400 MHz, CDCl3): δ = 7.59–7.53 (m,
4 H), 7.38–7.35 (m, 2 H), 7.30–7.23 (m, 2 H), 7.17 (d, J = 16.0 Hz,
1 H), 7.01 (d, J = 7.6 Hz, 1 H), 2.59 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.0, 155.0, 137.0, 136.7, 132.8, 128.7,
128.7, 128.0, 127.2, 121.8, 118.8, 24.4 ppm. HRMS (ESI) calcd. for
C14H14N [M + H]+ 196.1126; found 196.1128.
(E)-2-[2-(Quinolin-2-yl)vinyl]phenol (4ck): Yield 40.8 mg, 55%; yel-
low solid; m.p. 116–118 °C. 1H NMR (400 MHz, CDCl3): δ = 8.06
(t, J = 9.2 Hz, 2 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.71–7.67 (m, 1 H),
7.51–7.45 (m, 3 H), 7.36 (d, J = 7.6 Hz, 2 H), 7.29–7.25 (m, 1 H),
7.09–7.02 (m, 1 H), 6.96–6.83 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.0, 148.3, 137.0, 136.2, 136.0, 134.9, 132.9, 129.8,
129.2, 128.8, 128.6, 128.2, 127.5, 127.3, 126.8, 126.1, 119.4 ppm.
HRMS (ESI) calcd. for C17H14NO [M + H]+ 248.1075; found
248.1076.
(E)-2-Methyl-6-[2-(trifluoromethyl)styryl]pyridine
(4ab):
Yield
77.4 mg, 98%; yellow solid; m.p. 36–38 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.89–7.82 (m, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.60–
7.53 (m, 2 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H),
7.16 (d, J = 16.0 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 2.59 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.8, 153.1, 136.4,
134.5, 131.0, 130.6, 127.6, 126.9, 126.8, 126.6, 126.4, 124.9–124.7
(m), 121.5, 117.7, 22.9 ppm. HRMS (ESI) calcd. for C15H13F3N
[M + H]+ 264.1000; found 264.1001.
(E)-2-(2-Cyclohexylvinyl)quinoline (4cl): Yield 31.2 mg, 48%; yellow
1
(E)-4-[2-(6-Methylpyridin-2-yl)vinyl]benzonitrile
(4ac):
Yield
solid; m.p. 48–50 °C. H NMR (400 MHz, CDCl3): δ = 8.06 (d, J
59.5 mg, 89%; yellow solid; m.p. 133–135 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.57–7.50 (m, 6 H), 7.19–7.15 (m, 2 H), 7.00 (d, J =
7.6 Hz, 1 H), 2.52 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 158.5, 153.8, 141.2, 136.8, 132.4, 131.8, 130.2, 127.4, 122.6, 119.8,
118.9, 111.0, 24.6 ppm. HRMS (ESI) calcd. for C15H13N2 [M +
H]+ 221.1079; found 221.1080.
= 8.4 Hz, 1 H), 8.02 (d, J = 8.8 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1
H), 7.69–7.65 (m, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 7.48–7.44 (m, 1
H), 6.81–6.75 (m, 1 H), 6.70–6.65 (m, 1 H), 2.30–2.22 (m, 1 H),
1.91–1.70 (m, 6 H), 1.39–1.27 (4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 155.7, 147.0, 142.4, 135.1, 128.4, 128.0, 127.6, 126.4,
126.1, 124.8, 117.6, 40.1, 31.5, 25.1, 25.0 ppm. HRMS (ESI) calcd.
for C17H20N [M + H]+ 238.1596; found 238.1598.
(E)-2-Methyl-6-(3-nitrostyryl)pyridine (4ad): Yield 69.9 mg, 97%;
yellow solid; m.p. 108–110 °C. 1H NMR (400 MHz, CDCl3): δ =
8.42 (s, 1 H), 8.12 (dd, J = 1.2, J = 8.0 Hz, 1 H), 7.87 (d, J =
8.0 Hz, 1 H), 7.69–7.60 (m, 2 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.33–
7.26 (m, 2 H), 7.09 (d, J = 8.0 Hz, 1 H), 7.62 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.3, 153.8, 148.7, 138.5, 137.4,
132.8, 130.3, 129.6, 124.4, 122.8, 122.6, 121.5, 119.6, 24.2 ppm.
HRMS (ESI) calcd. for C14H13N2O2 [M + H]+ 241.0977; found
241.0978.
(E)-2-[2-(Furan-2-yl)vinyl]quinoline (4cm): Yield 31.2 mg, 72%; yel-
1
low solid; m.p. 52–54 °C. H NMR (400 MHz, CDCl3): δ = 8.09–
8.04 (m, 2 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.68 (dt, J = 1.2, 8.0 Hz,
1 H), 7.58–7.45 (m, 4 H), 7.27 (d, J = 15.6 Hz, 1 H), 6.54–6.53 (m,
1 H), 6.47–6.46 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
155.6, 152.8, 148.3, 143.2, 136.3, 129.7, 129.2, 127.5, 127.3, 126.8,
126.1, 121.7, 119.9, 112.0, 111.2 ppm. HRMS (ESI) calcd. for
C15H12NO [M + H]+ 222.0919; found 222.0920.
(E)-8-Nitro-2-styrylquinoline (4da): Yield 74.6 mg, 90%; yellow so-
lid; m.p. 132–134 °C. H NMR (400 MHz, CDCl3): δ = 8.16 (d, J
(E)-2-(3-Fluorostyryl)-6-methylpyridine (4ae): Yield 56.9 mg, 89%;
yellow solid; m.p. 100–102 °C. 1H NMR (400 MHz, CDCl3): δ =
1
= 8.8 Hz, 1 H), 7.98 (dd, J = 1.2, 7.6 Hz, 1 H), 7.94 (dd, J = 1.2, 7.65 (d, J = 7.6 Hz, 1 H), 7.58 (d, J = 16.0 Hz, 1 H), 7.37–7.27 (m,
8.0 Hz, 1 H), 7.80 (d, J = 16.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 5 H), 7.09 (d, J = 7.6 Hz, 1 H), 7.02–6.97 (m, 1 H), 2.66 (s, 3
7.62 (d, J = 6.8 Hz, 2 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.42–7.38 (m,
2 H), 7.36–7.30 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.8, 153.0, 137.8 (d, J = 7.7 Hz), 136.5, 131.0, 129.1 (d, J =
158.0, 148.0, 139.6, 136.7, 136.2, 136.0, 131.5, 129.2, 128.8, 128.1, 7.5 Hz), 127.4, 122.1, 121.3, 118.2, 114.2 (d, J = 21.2 Hz), 112.4 (d,
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.0 (d, J = 244.1 Hz),
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O40073
/KAP1
Date: 26-03-14 17:01:41
Pages: 12
Benzylic Reactions of 2-Methylazaarenes
J = 21.6 Hz), 23.0 ppm. HRMS (ESI) calcd. for C14H13FN [M + (d, J = 4.4 Hz, 1 H), 7.95 (dd, J = 2.0, 16.0 Hz, 1 H), 7.86 (d, J =
H]+ 214.1032; found 214.1030.
7.6 Hz, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.69 (d, J = 7.6 Hz, 1 H),
7.59–7.55 (m, 2 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.32–7.26 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.4, 148.2, 137.9,
135.2, 132.1, 130.6, 129.8, 128.2, 126.8 (d, J = 225.3 Hz), 127.6,
126.0 (t, J = 5.6 Hz), 125.7, 122.9, 122.0 ppm. HRMS (ESI) calcd.
for C14H11F3N [M + H]+ 250.0844; found 250.0843.
(E)-2-(4-Fluorostyryl)-6-methylpyridine (4af): Yield 51.1 mg, 80%;
yellow solid; m.p. 121–123 °C. 1H NMR (400 MHz, CDCl3): δ =
7.72 (d, J = 7.6 Hz, 1 H), 7.63–7.57 (m, 3 H), 7.43–7.36 (m, 2 H),
7.13 (d, J = 8.0 Hz, 1 H), 7.09–7.05 (m, 2 H), 2.72 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 162.8 (d, J = 246.8 Hz), 158.0,
154.7, 137.2 (d, J = 8.8 Hz), 132.9, 131.7 (d, J = 10.1 Hz), 128.7
(d, J = 7.9 Hz), 127.5 (d, J = 12.3 Hz), 124.2 (d, J = 50.6 Hz),
121.9, 118.8, 115.7 (d, J = 21.7 Hz), 24.3 ppm. HRMS (ESI) calcd.
for C14H13FN [M + H]+ 214.1032; found 214.1033.
(E)-4-[2-(Pyridin-2-yl)vinyl]benzonitrile (4bc): Yield 54.4 mg, 88%;
yellow solid; m.p. 126–128 °C. 1H NMR (400 MHz, CDCl3): δ =
8.64 (d, J = 4.4 Hz, 1 H), 7.77 (dd, J = 1.6, 7.6 Hz, 1 H), 7.71–7.66
(m, 5 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.31–7.25 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 154.3, 149.6, 141.1, 137.1, 132.5,
131.0, 127.5, 123.0, 118.9, 111.3 ppm. HRMS (ESI) calcd. for
C14H11N2 [M + H]+ 207.0922; found 207.0920.
(E)-2-Methyl-6-(3-methylstyryl)pyridine (4ag): Yield 45.2 mg, 72%;
yellow solid; m.p. 95–97 °C. 1H NMR (400 MHz, CDCl3): δ =
7.56–7.51 (m, 2 H), 7.27–7.21 (m, 2 H), 7.16 (d, J = 16.0 Hz, 1 H),
7.10 (d, J = 7.6 Hz, 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 2.58 (s, 3 H),
2.37 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.8, 154.9,
138.2, 137.3, 136.5, 133.3, 129.3, 128.6, 127.9, 127.4, 124.4, 121.9,
118.8, 24.2, 21.4 ppm. HRMS (ESI) calcd. for C15H16N [M + H]+
210.1283; found 210.1284.
(E)-2-(2-Nitrostyryl)pyridine (4bd): Yield 61.1 mg, 90%; yellow so-
1
lid; m.p. 91–94 °C. H NMR (400 MHz, CDCl3): δ = 8.64 (d, J =
4.4 Hz, 1 H), 8.04–7.98 (m, 2 H), 7.80 (d, J = 7.6 Hz, 1 H), 7.71
(dt, J = 1.6, 7.6 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 1 H), 7.50 (d, J =
8.0 Hz, 1 H), 7.48–7.44 (m, 1 H), 7.23–7.20 (m, 1 H), 7.17 (d, J =
16.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.5, 148.0,
143.2, 142.9, 134.9, 134.1, 130.6, 130.4, 129.5, 125.1, 125.0, 124.5,
122.9 ppm. HRMS (ESI) calcd. for C13H11N2O2 [M + H]+
227.0821; found 227.0823.
(E)-2-Methyl-6-(4-methylstyryl)pyridine (4ah): Yield 45.8 mg, 73%;
yellow solid; m.p. 106–108 °C. 1H NMR (400 MHz, CDCl3): δ =
7.71 (t, J = 7.6 Hz, 1 H), 7.60 (d, J = 16.0 Hz, 1 H), 7.52 (s, 1 H),
7.50 (s, 1 H), 7.45–7.35 (m, 2 H), 7.20 (s, 1 H), 7.18 (s, 1 H), 7.10
(d, J = 7.6 Hz, 1 H), 2.71 (s, 3 H), 2.37 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.0, 154.5, 138.9, 138.3, 134.4, 133.4,
129.5, 127.4, 125.0, 122.1, 118.8, 23.5 ppm. HRMS (ESI) calcd. for
C15H16N [M + H]+ 210.1283; found 210.1285.
(E)-2-(3-Nitrostyryl)pyridine (4be): Yield 62.4 mg, 92%; yellow so-
1
lid; m.p. 128–130 °C. H NMR (400 MHz, CDCl3): δ = 8.65 (d, J
= 3.2 Hz, 1 H), 8.44 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.90 (d, J
= 7.6 Hz, 1 H), 7.81–7.77 (m, 2 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.49
(d, J = 7.6 Hz, 1 H), 7.36–7.27 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 152.8, 147.8, 147.4, 137.2, 136.6, 132.0, 129.6, 128.8,
122.0, 121.6, 120.2 ppm. HRMS (ESI) calcd. for C13H11N2O2 [M
+ H]+ 227.0821; found 227.0820.
(E)-2-(4-Methoxystyryl)-6-methylpyridine (4ai): Yield 38.5 mg,
54%; yellow solid; m.p. 51–53 °C. H NMR (400 MHz, CDCl3): δ
1
= 7.69 (t, J = 7.6 Hz, 1 H), 7.62–7.54 (m, 3 H), 7.41 (d, J = 7.6 Hz,
1 H), 7.34 (d, J = 16.0 Hz, 1 H), 7.07 (d, J = 7.2 Hz, 1 H), 6.91 (s,
1 H), 6.89 (s, 1 H), 3.83 (s, 3 H), 2.70 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.8, 158.1, 155.4, 136.6, 131.9, 129.6,
128.4, 126.3, 121.3, 118.5, 114.2, 55.2, 24.7 ppm. HRMS (ESI)
calcd. for C15H16NO [M + H]+ 226.1232; found 226.1230.
(E)-2-(3-Fluorostyryl)pyridine (4bf): Yield 53.2 mg, 89%; yellow so-
1
lid; m.p. 49–51 °C. H NMR (400 MHz, CDCl3): δ = 8.62 (d, J =
4.0 Hz, 1 H), 7.75 (t, J = 7.6 Hz, 1 H), 7.67 (d, J = 16.0 Hz, 1 H),
7.46 (d, J = 8.0 Hz, 1 H), 7.37–7.20 (m, 5 H), 7.03–7.00 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.1 (d, J = 244.2 Hz),
154.4, 148.4, 138.6 (d, J = 7.7 Hz), 137.8, 132.8, 130.3, 130.2, 127.7,
123.3 (d, J = 2.3 Hz), 122.6, 115.5 (d, J = 21.3 Hz), 113.5 (d, J =
21.7 Hz) ppm. HRMS (ESI) calcd. for C13H11FN [M + H]+
200.0876; found 200.0878.
(E)-2-(2-Cyclohexylvinyl)-6-methylpyridine (4aj): Yield 26.0 mg,
43%; yellow solid; m.p. 52–54 °C. H NMR (400 MHz, CDCl3): δ
1
= 7.83 (t, J = 7.6 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.18 (d, J =
7.2 Hz, 1 H), 6.99 (d, J = 16.0 Hz, 1 H), 6.84–6.79 (m, 1 H), 2.80
(s, 3 H), 2.32–2.25 (m, 1 H), 1.86–1.68 (m, 6 H), 1.24–1.14 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.5, 152.0, 147.7,
141.0, 122.4, 120.5, 117.9, 40.5, 31.1, 28.7, 24.9, 24.7 ppm. HRMS
(ESI) calcd. for C14H20N [M + H]+ 202.1596; found 202.1595.
(E)-2-(4-Fluorostyryl)pyridine (4bg): Yield 52.0 mg, 87%; yellow so-
1
lid; m.p. 81–83 °C. H NMR (400 MHz, CDCl3): δ = 8.60 (d, J =
4.4 Hz, 1 H), 7.70 (dd, J = 1.6, 8.0 Hz, 1 H), 7.63 (d, J = 16.0 Hz,
1 H), 7.57–7.54 (m, 2 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J =
5.6, 7.6 Hz, 1 H), 7.14–7.04 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 162.9 (d, J = 247.2 Hz), 154.7, 148.4, 137.6, 132.6 (d,
J = 10.9 Hz), 129.5 (d, J = 7.7 Hz), 128.9 (d, J = 8.1 Hz), 126.3,
123.7, 122.3, 115.7 (d, J = 21.9 Hz) ppm. HRMS (ESI) calcd. for
C13H11FN [M + H]+ 200.0876; found 200.0875.
(E)-2-[2-(Furan-2-yl)vinyl]-6-methylpyridine (4ak): Yield 36.1 mg,
65%; yellow solid; m.p. 84–86 °C. H NMR (400 MHz, CDCl3): δ
1
= 7.51 (d, J = 7.6 Hz, 1 H), 7.46–7.42 (m, 2 H), 7.11 (d, J = 7.6 Hz,
1 H), 7.05 (d, J = 16.0 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 6.45–
6.42 (m, 2 H), 2.56 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 157.0, 153.4, 151.9, 141.8, 136.0, 124.8, 120.7, 119.3, 118.3, 110.8,
109.6, 23.3 ppm. HRMS (ESI) calcd. for C12H12NO [M + H]+
186.0919; found 186.0920.
(E)-2-(3-Methylstyryl)pyridine (4bh): Yield 36.3 mg, 62%; yellow
1
solid; m.p. 76–78 °C. H NMR (400 MHz, CDCl3): δ = 8.59 (d, J
= 4.4 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.65 (d, J = 16.0 Hz, 1
H), 7.46 (d, J = 8.0 Hz, 1 H), 7.40–7.38 (m, 2 H), 7.26 (t, J =
7.6 Hz, 1 H), 7.23–7.17 (m, 2 H), 7.13 (d, J = 7.6 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.0, 148.3, 138.3, 137.7, 136.2,
129.6, 128.7, 128.0, 126.2, 125.1, 124.6, 122.3, 122.2, 21.4 ppm.
HRMS (ESI) calcd. for C14H14N [M + H]+ 196.1126; found
196.1128.
(E)-2-Styrylpyridine (4ba): Yield 41.9 mg, 77%; yellow solid; m.p.
89–91 °C. H NMR (400 MHz, CDCl3): δ = 8.60 (d, J = 3.2 Hz, 1
1
H), 7.78 (t, J = 7.6 Hz, 1 H), 7.72 (d, J = 16.4 Hz, 1 H), 7.61–7.59
(m, 2 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.40–7.36 (m, 2 H), 7.33–7.29
(m, 1 H), 7.27–7.20 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 154.4, 148.5, 135.5, 135.4, 131.5, 127.6, 127.2, 126.8, 126.0,
121.0, 120.9 ppm. HRMS (ESI) calcd. for C13H12N [M + H]+
182.0970; found 182.0972.
(E)-2-(4-Methylstyryl)pyridine (4bi): Yield 38.7 mg, 66%; yellow so-
1
(E)-2-[2-(Trifluoromethyl)styryl]pyridine (4bb): Yield 71.8 mg, 96%; lid; m.p. 83–85 °C. H NMR (400 MHz, CDCl3): δ = 8.59 (d, J =
yellow solid; m.p. 83–85 °C. 1H NMR (400 MHz, CDCl3): δ = 8.63 4.0 Hz, 1 H), 7.66–7.58 (m, 2 H), 7.49 (s, 1 H), 7.47 (s, 1 H), 7.37
Eur. J. Org. Chem. 0000, 0–0
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Pages: 12
D. Mao, G. Hong, S. Wu, X. Liu, J. Yu, L. Wang
FULL PAPER
(d, J = 8.0 Hz, 1 H), 7.19–7.11 (m, 4 H), 2.36 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 155.8, 149.6, 138.4, 136.6, 133.9,
132.7, 129.5, 127.1, 127.0, 122.0, 121.9, 21.4 ppm. HRMS (ESI)
calcd. for C14H14N [M + H]+ 196.1126; found 196.1125.
9192–9199; c) R. N. Gupta, I. D. Spenser, Can. J. Chem. 1907,
45, 1275–1285; d) O. Meth-Cohn, C. C. Yau, C.-Y. Yu, J. Het-
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Borghese, B. Bonnier, A. Mockel, F. Napora, Org. Process Res.
Dev. 2006, 10, 776–783; b) J. M. McNamara, J. L. Leazer, M.
Bhupathy, J. S. Amato, R. A. Reamer, P. J. Reider, E. J. J. Gra-
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E. G. Corley, R. K. Anderson, R. D. Larsen, T. R. Verhoeven,
P. J. Reider, J. Org. Chem. 1993, 58, 3731–3735; d) J. Y. Gauth-
ier, T. Jones, E. Champion, L. Charette, R. Dehaven, A. W.
Ford-Hutchinson, K. Hoogsteen, A. Lord, P. Masson, H. Pie-
chuta, S. S. Pong, J. P. Springer, M. Thérien, R. Zamboni,
R. N. Young, J. Med. Chem. 1990, 33, 3841–3845; e) R. Zam-
boni, M. Belley, E. Champion, L. Charette, R. DeHaven, R.
Frenetta, J. Y. Gauthier, T. R. Jonea, S. Leger, P. Maaeon, C. S.
McFarlane, K. Metters, S. S. Pong, H. Piechuta, J. Rochch, M.
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35, 3832–3844.
[4]
[5]
(E)-2-(4-Methoxystyryl)pyridine (4bj): Yield 34.2 mg, 54%; yellow
1
solid; m.p. 48–51 °C. H NMR (400 MHz, CDCl3): δ = 8.59 (d, J
= 4.0 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.64 (d, J = 16.0.0 Hz, 1
H), 7.56 (s, 1 H), 7.54 (s, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.17–7.14
(m, 1 H), 7.09 (d, J = 16.0 Hz, 1 H), 6.94 (s, 1 H), 6.91 (s, 1 H),
3.84 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.0, 155.6,
148.8, 137.0, 133.0, 129.2, 128.6, 125.0, 121.8, 121.7, 114.2,
55.3 ppm. HRMS (ESI) calcd. for C14H14NO [M + H]+ 212.1075;
found 212.1077.
(E)-2-[2-(Pyridin-2-yl)vinyl]phenol (4bk): Yield 34.2 mg, 48%; yel-
low solid; m.p. 91–93 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
8.64 (d, J = 4.4 Hz, 1 H), 7.84–7.69 (m, 3 H), 7.58 (d, J = 8.0 Hz,
1 H), 7.45 (dd, J = 1.2, 8.0 Hz, 1 H), 7.22–7.19 (m, 1 H), 7.15–7.11
(m,
1 H), 6.89–6.84 (m, 2
H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 155.4, 149.3, 136.9, 129.4, 127.5, 127.2, 127.1,
123.0, 122.1, 119.4, 115.8 ppm. HRMS (ESI) calcd. for C13H12NO
[M + H]+ 198.0919; found 198.0920.
[6]
[7]
For reviews, see: a) I. Nakamura, Y. Yamamoto, Chem. Rev.
2004, 104, 2127–2198; b) G. Zeni, R. C. Larock, Chem. Rev.
2006, 106, 4644–4680.
(E)-2-(2-Cyclohexylvinyl)pyridine (4bl): Yield 22.5 mg, 40%; yellow
solid; m.p. 50–52 °C. H NMR (400 MHz, CDCl3): δ = 8.65 (s, 1
1
H), 8.25 (s, 1 H), 7.85 (d, J = 6.8 Hz, 1 H), 7.64 (s, 1 H), 7.24–7.18
(m, 1 H), 6.96 (d, J = 16.0 Hz, 1 H), 2.38–2.33 (s, 1 H), 1.87–1.78
(m, 6 H), 1.25–1.05 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 154.0, 145.9, 143.5, 137.6, 124.0, 121.0, 120.5, 40.2, 31.3, 25.0,
24.8 ppm. HRMS (ESI) calcd. for C13H18N [M + H]+ 188.1439;
found 188.1440.
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Ueda, S. Yanagisawa, K. Itami, C.-J. Li, Chem. Eur. J. 2009,
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a) J. J. Mousseau, A. Larivée, A. B. Charette, Org. Lett. 2008,
10, 1641–1643; b) D. J. Schipper, L.-C. Campeau, K. Fagnou,
Tetrahedron 2009, 65, 3155–3164.
a) B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia, H. Hu-
ang, J. Am. Chem. Soc. 2010, 132, 3650–3651; b) T. Niwa, H.
Yorimitsu, K. Oshima, Angew. Chem. Int. Ed. 2007, 46, 2643–
2645; Angew. Chem. 2007, 119, 2697; c) J.-Y. Liu, H.-Y. Niu, S.
Wu, G.-R. Qu, H.-M. Guo, Chem. Commun. 2012, 48, 9723–
9725.
(E)-2-[2-(Furan-2-yl)vinyl]pyridine (4bm): Yield 31.8 mg, 62%; yel-
low solid; m.p. 60–62 °C. 1H NMR (400 MHz, CDCl3): δ = 8.64
(d, J = 5.2 Hz, 1 H), 8.13 (t, J = 8.0 Hz, 1 H), 8.00 (d, J = 16.0 Hz,
1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.54–7.50 (m, 2 H), 7.21 (d, J =
16.0 Hz, 1 H), 6.79 (d, J = 6.8 Hz, 1 H), 6.52 (t, J = 1.6 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.3, 152.9, 149.7,
142.9, 136.5, 125.9, 122.5, 121.9, 120.2, 111.9, 110.7 ppm. HRMS
(ESI) calcd. for C11H10NO [M + H]+ 172.0762; found 172.0760.
[8]
[9]
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of all products.
Acknowledgments
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a) B. Qian, D. J. Shi, L. Yang, H. M. Huang, Adv. Synth. Catal.
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This research was financially supported by the National Nature
Science Foundation of China (NSFC) (grant numbers 21272069,
20672035) and the Fundamental Research Funds for the Central
Universities and Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sci-
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10
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Benzylic Reactions of 2-Methylazaarenes
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Received: January 16, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O40073
/KAP1
Date: 26-03-14 17:01:41
Pages: 12
D. Mao, G. Hong, S. Wu, X. Liu, J. Yu, L. Wang
FULL PAPER
Direct C–H Functionalization
D. Mao, G. Hong, S. Wu, X. Liu, J. Yu,
L. Wang* ........................................ 1–12
Lewis-Acid-Catalyzed Benzylic Reactions
of 2-Methylazaarenes with Aldehydes
Lewis-acid-promoted benzylic reactions of
2-methylazaarenes with common aldehydes
have been extensively investigated for the
first time. Series of azaarene derivatives in-
cluding 2-(pyridin-2-yl)ethanols and 2-alk-
enylazaarenes were synthesized with wide
substrate scopes by employing different
catalysts that were optimized on the basis
of the structures of the 2-methylazaarenes
and the products.
Keywords: Nitrogen heterocycles / Aldol re-
actions / C–H activation
12
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