TMEDA-assisted effective direct ortho arylation of electron-deficient N -heteroarenes with aromatic grignard reagents

Article abstract of DOI:10.1021/jo400152f

In the addition of TMEDA in toluene, aryl Grignards could effectively and site-specifically ortho-arylate electron-deficient heteroarenes under mild conditions. This endeavor successfully changed the old low-yielding reaction, aryl Grignard addition to N-heteroarenes, into an efficient procedure for heterobiaryls. The combination of the inexpensive aryl Grignards, TMEDA, the cost-free air, no use of any transition-metal catalyst, the mild reaction conditions, and the high-yielding gram-scale results enables this new procedure to be cost-effective and potentially utilizable in industry.

Full text of DOI:10.1021/jo400152f

Article
pubs.acs.org/joc
TMEDA-Assisted Effective Direct Ortho Arylation of Electron-
Deficient N‑Heteroarenes with Aromatic Grignard Reagents
Fang-Fang Zhuo,† Wen-Wen Xie,† Yong-Xin Yang,† Lei Zhang,† Pei Wang,† Rui Yuan,†
and Chao-Shan Da*,†,‡,§
†Institute of Biochemistry & Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000,
People’s Republic of China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
§Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou 730000,
People’s Republic of China
S
* Supporting Information
ABSTRACT: In the addition of TMEDA in toluene, aryl
Grignards could effectively and site-specifically ortho-arylate
electron-deficient heteroarenes under mild conditions. This
endeavor successfully changed the old low-yielding reaction,
aryl Grignard addition to N-heteroarenes, into an efficient
procedure for heterobiaryls. The combination of the inexpensive aryl Grignards, TMEDA, the cost-free air, no use of any
transition-metal catalyst, the mild reaction conditions, and the high-yielding gram-scale results enables this new procedure to be
cost-effective and potentially utilizable in industry.
strategy of aryl metallics to heteroarenes at high reaction
temperatures.9
INTRODUCTION
■
Currently, direct ortho arylations of electron-deficient
N-heteroarenes, such as pyridines, quinolines, and isoquinolines,
are attracting intensive research interest because the target
heterobiaryls are central synthetic motifs of biologically active
molecules1 and useful materials.2 Several different methods have
been developed to prepare heterobiaryls from electron-deficient
N-heteroarenes. Naturally, the successful cross-coupling meth-
ods of aryl halides with aryl metallics allowed access to these
heterobiaryls, which comprised ortho-metalated pyridine or
quinoline coupling with aryl halides3 and ortho halo or tosyl
heteroarenes with aryl metallics.4 The common limitation of
these methods is the indispensable preparation of ortho-
halogenated or -tosylated heteroarenes prior to coupling.
Ortho C−H functionalization with aryl halides5a−d or arylbo-
ronic acids5e catalyzed by transition metals was another disclosed
protocol with moderate to good yields, in which a higher than
100 °C reaction temperature was generally needed. N-Oxides are
effective surrogates of activated electron-deficient arenes; the
cross-coupling of N-oxide-activated pyridines with haloarenes or
tosylarenes was the most developed procedure in the catalysis of
transition metals.6 Other reported N-activations of pyridines
comprised N-phenacyl and imino modes.7 Furthermore,
N-oxidized pyridine direct oxidative coupling with unactivated
arenes was recently reported.8 Activated N-heteroarenes with
N-oxides considerably facilitated the direct ortho arylation of
heteroarenes, but as the prior preparation of N-oxides and later
elimination of the activating group was apparently unavoidable,
this major limitation unavoidably increased the cost of the
protocols and reduced their applicability. The additional transition-
metal-catalyzed ortho arylation comprised the 1,2-addition/oxidation
All of these aforementioned protocols were chiefly based on
transition-metal catalysis. To date the transition-metal-free
procedures have mainly comprised direct ortho addition of aryl
Grignards to N-oxide activated pyridines10 and KO-t-Bu
promoted direct coupling of pyrazine and pyridine with
iodoarenes.11 We are particularly interested in the transition-
metal-free direct arylation of unactivated N-heteroarenes with
aryl Grignards, because it has the advantages of no need for
preparation of ortho halo or tosyl heteroarenes, no need for prior
installation of activating groups and subsequent removal, and no
need for the preparation of scarecely available and unstable
heteroaryl metallics. Obviating the use of expensive and
potentially toxic transition metals would further effectively
eliminate the serious demand for their complete removal in the
latter stages of the pharmaceutical synthesis. Additionally,
inexpensive and readily available aryl Grignards and no need
for very high reaction temperatures would undoubtedly reduce
the cost and facilitate future industrial applications. It has long
been known that aryl Grignards or lithiums can undergo 1,2-
addition to unactivated N-heteroarenes and successive oxidation
to furnish ortho arylation with oxidizing reagents; however, the
low to moderate arylated yields render this procedure nearly
impractical.12 This situation stimulated the discovery of the
aforementioned various methods for bypassing this procedure.
Up to today, this procedure is basically undeveloped and remains
a great challenge. On the basis of our recent research experience
Received: January 23, 2013
© XXXX American Chemical Society
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with Grignards,13 we envisioned that some proper additive would
probably enhance the arylation and upgrade the old procedure to
be an efficient one. In this work we finally found that TMEDA
could meet this serious requirement very well. This procedure is
a good complement to the reported protocols for heterobiaryl
preparation in a low-cost manner.
quinoline and thus increases the yield. The cost-free air not only
substantially caused the protocol to be environmentally friendly
but also greatly decreased the expense of the procedure.
With the optimized reaction conditions, the scope of aryl
Grignards was first evaluated with quinoline (Table 2; 1−13). As
can be seen, normally aryl Grignards with electron-donating
groups afforded excellent yields, while those with electron-
withdrawing groups gave slightly lower yields. Heterobiaryls with
two heteroarene units were mainly obtained with the activated
deficient heteroarenes in transition-metal catalysis.6c,d,7b,8b,10c
The transition-metal-catalyzed addition/oxidation procedures
using orgnometallics did not report similar target products.9
Herein the hard-to-prepare heteroaryl Grignards were synthe-
sized using Knochel’s method4a,14 and heterobiaryls with two
heteroarene units were thereby obtained in good to high yield
(11−13). Then quinoline derivatives were investigated (14−24).
3-Bromoquinoline always gave high yields with various aryl
Grignards, and the highest yield was 96% (14−19). Methyl-
substituted quinolines gave good to high yields with different aryl
Grignards (20−24).
Second, we evaluated the Grignard addition to isoquinolines
(Table 3). The addition reaction was fully site-specific; it only
gave isoquinolines with 1-arylation. For aryl Grignards, the
highest yield was 64% with 4-MeC6H4MgBr (26). Bromo-
substituted isoquinoline gave higher yields than isoquinoline
itself, and 4-MeC6H4MgBr again gave the highest yield (30).
Unactivated pyridines are normally difficult substrates.12 We
next explored the direct ortho arylation of pyridines. Pyridine
itself failed to give the ortho coupling product. Two 3-substituted
pyridines were further investigated (Scheme 1). They both
resulted in moderate yields with 6-addition, probably owing to
the steric hindrance.
Quinoxaline is an interesting scaffold for many key materials
and pharmacological compounds with the inclusion of two
nitrogen atoms.15 Recently, 2,3-diarylated quinoxalines were of
particular interest for their proportionation of radical anions.16
Our protocol could readily furnish these ortho-diarylated
quinoxalines in excellent yield at 50 °C (Table 4). In contrast,
the reaction temperature was much milder than that for the
reported transition-metal catalytic version and diarylation was
exclusively afforded in this work.9b It is notable that the
transition-metal-catalyzed cross-coupling of halogenated qui-
noxaline with aryl Grignards4a and KO-t-Bu-promoted coupling
of quinoxaline with iodobenzene11 both only afforded
monoarylated quinoxalines. Herein, even the heteroaryl
Grignard resulted in high yield. To our knowledge, this is the
first report about a heteroarene coupling with quinoxaline to
obtain 2,3-diarylated heterotriaryls.
RESULTS AND DISCUSSION
■
We screened the solvents, and the results showed that toluene
was optimal (THF was removed under vacuum and then toluene
was introduced). Toluene gave a 76% isolated yield, much higher
than that for THF (Table 1, entries 1−3). Then in toluene, a
a
Table 1. Optimization of the Reaction Conditions
amt of PhMgBr
(mmol)
additive (amt
b
temp
yield
c
entry
(mmol))
solvent
THF
(°C)
(%)
1
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.45
0.6
0.75
1.05
1.2
0.9
0.9
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
30
70
47
62
76
74
29
88
80
51
79
84
84
83
74
73
78
82
88
89
55
84
d
2
DCE
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
4
NMM (0.3)
5
DMAP (0.3)
6
TMEDA (0.3)
BDMAEE (0.3)
HMTA (0.3)
7
8
9
TMEDA (0.18)
TMEDA (0.24)
TMEDA (0.36)
TMEDA (0.42)
TMEDA (0.48)
TMEDA (0.3)
TMEDA (0.3)
TMEDA (0.3)
TMEDA (0.3)
TMEDA (0.3)
TMEDA (0.3)
10
11
12
13
14
15
16
17
18
19
20
TMEDA (0.3)
a
b
0.3 mmol of quinoline was used. NMM is N-methylmorpholine,
DMAP is 4-dimethylaminopryidine, TMEDA is tetramethylethylenedi-
amine, BDMAEE is 2,2′-oxybis-(N,N-dimethylethanamine), and
c
HMTA is hexamethylenetetramine(methenamine), respectively. Iso-
d
lated yield. DCE is 1,2-dichloroethane.
series of chelating additives were screened (entries 4−8). Only
TMEDA and BDMAEE enhanced the yield, and TMEDA
achieved the highest yield (up to 88%). TMEDA, as an easily
available low-cost chelating additive, made this new procedure
inexpensive. The load experiment of TMEDA showed that 1.0
equiv of TMEDA with respect to quinoline was optimal (entries
6 and 9−13). The amount of aryl Grignards used had a great
influence on the yield (entries 14−18). The observation
indicated that 3.0 equiv of PhMgBr was satisfactory (entry 6);
lower amounts of Grignards led to decreased yield, but more than
3.0 equiv did not raise the yield any further. Finally, the reaction
temperature was screened and 50 °C proved to be ideal (entries
6, 19, and 20). Normally, a small amount of 1,2-dihydroquinoline
as an intermediate was included in the reaction mixture, but it
was not necessary to add any additional oxidant. After the
reaction was quenched, keeping the reaction mixture in the air for
at most 12 h changes this small amount of impurity into oxidized
Finally, the easily handled, readily available, and inexpensive
Grignard reagents and the mild reaction conditions spurred us to
explore the gram-scale preparation of the heterobiaryls. To our
gratification, 2.0 g of quinoline successfully afforded a high 83%
yield (Scheme 2). This result renders this protocol highly
potentially useful in industry.
CONCLUSION
■
In conclusion, we have demonstrated that TMEDA could
efficiently enhance the direct ortho arylation of electron-deficient
N-heteroarenes with aryl Grignards under mild reaction
conditions, successfully upgrading the old low-yielding proce-
dure to be a practical method in the preparation of ortho-arylated
heterobiaryls as well as the interesting quinoxaline-derived
heterotriaryls. The readily available and inexpensive aryl
B
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a
Table 2. Aryl Grignard Addition to Quinolines
a
ArMgBr/quinoline/TMEDA = 0.9/0.3/0.3 mmol. A 1.0 mL portion of toluene was used, and the reaction was carried out for 10 h at 50 °C. The
crude product contained a small amount of 1,2-dihydroquinoline derivatives, which was oxidized to quinoline in air for 12 h at ambient temperature.
b
c
d
The yield is the isolated yield. The reaction time was 17 h. ArMgBr/quinoline/TMEDA = 1.5/0.3/0.3, 36 h. ArMgBr/quinoline/TMEDA = 1.5/
e
0.3/0.3, 24 h. The reaction time was 24 h at 70 °C.
(TLC); column chromatography purifications were carried out using
silica gel. All reagents were purchased from commercial vendors unless
otherwise stated. Grignard reagents were freshly prepared from
magnesium powder with the corresponding bromides according to
the established procedure17 or Knochel’s method, and their
concentrations were determined by titration according to Love’s
method.18 Melting points are uncorrected and were recorded on an
X-4 melting point apparatus. HR-MS were measured by the ESI method
with a Q-TOF mass spectrometer. 1H NMR and 13C NMR spectra were
measured on 400 and 300 MHz spectrometers (NMR in CDCl3 with
TMS as an internal standard), and resonances are given in ppm.
General Procedure for the Arylation of the N-Heteroarenes.
The aryl Grignard was prepared according to the established
procedure,17 and their concentrations were determined by titration
according to Love’s method.18 The aryl Grignard (0.9 mmol) in THF
Grignards and TMEDA, the cost-free air, the obviation of the
need for a transition metal or prior installation and later
elimination of any activating group, and the mild reaction
conditions are prominent features of this report; these features
make this protocol very cost-effective. Furthermore, the
successful gram-scale experiment endows this protocol with
potential utility in industry for pharmaceutical and material
synthesis.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out under an
argon atmosphere, and solvents were dried according to the established
procedures. Reactions were monitored by thin-layer chromatography
C
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a
Table 3. Aryl Grignard Addition to Isoquinolines
a
ArMgBr/quinoline/TMEDA = 0.9/0.3/0.3 mmol. A 1.0 mL portion of toluene was used, and the reaction was carried out for 12 h at 70 °C for 25−
27 and for 17 h at 50 °C for 28−31. The crude product contained a small amount of 1,2-dihydroquinoline derivatives, which was able to be oxidized
to quinoline in air for 12 h at ambient temperature. The yield is the isolated yield.
Scheme 1. Aryl Grignard Addition to Pyridines
Scheme 2. Gram-Scale Ortho Arylation of Quinoline with the
Grignard
Grignards were prepared according to Knochel’s method,14 and their
concentrations were determined by titration according to Love’s
method.18 The heteroaryl aryl Grignard (1.5 mmol) in THF was
condensed to near-dryness under vacuum, and 1.0 mL of toluene was
added to dissolve it under an argon atmosphere. Then TMEDA (0.3
mmol, 45.6 μL) was introduced into the Grignard reagent solution at
room temperature. The mixture was stirred for 30 min, and the N-
heteroarene (0.3 mmol) was successively introduced. The reaction
mixture was stirred for 36 h at 50 °C. After the completion was checked
with TLC, the reaction mixture was cooled to 0 °C and aqueous NH4Cl
was added dropwise to quench the reaction; then the mixture so
obtained was stirred in the open air. After about 12 h the reaction
mixture was checked with TLC, and then the aqueous layer was
extracted three times with ethyl acetate. The organic layers were
combined, washed successively with water and a small amount of brine,
and dried with anhydrous Na2SO4. The combined filtrates were
concentrated under vacuum to give the crude product. Finally
purification by column chromatography afforded the target hetero-
biaryls 12, 13, 35, and 36, respectively.
was condensed to near-dryness under vacuum, and 1.0 mL of toluene
was added to dissolve it under an argon atmosphere. Then TMEDA (0.3
mmol, 45.6 μL) was introduced into the Grignard reagent solution at
room temperature. The mixture was stirred for 30 min, and the N-
heteroarene (0.3 mmol) was successively introduced. The reaction
mixture was stirred for 10 h at 50 °C. After the completion was checked
with TLC, the reaction mixture was cooled to 0 °C and aqueous NH4Cl
was added dropwise to quench the reaction; then the mixture so
obtained was stirred in the open air. After about 12 h the reaction
mixture was checked with TLC, and then the aqueous layer was
extracted three times with ethyl acetate. The organic layers were
combined, washed successively with water and a small amount of brine,
and dried with anhydrous Na2SO4. The combined filtrates were
concentrated under vacuum to give the crude product. Finally
purification by column chromatography afforded the target heterobiaryl.
General Procedure for the Arylation of the N-Heteroarene
with the Heteroaryl Grignard Prepared with LiCl. The heteroaryl
a
Table 4. Aryl Grignard Addition to Quinoxaline
a
b
c
ArMgBr/quinoxaline/TMEDA = 0.9/0.3/0.3 mmol. For 35 and 36, 5.0 equiv Grignard was used. The yield is the isolated yield. 16 h. 36 h.
D
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2-Phenylquinoline (1; Table 2):4d,5b column chromatography, silica
(85.5 mg); mp 87 °C; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.11
(d, J = 8.4 Hz, 1H), 7.74−7.63 (m, 4H), 7.53 (t, J = 7.6 Hz, 1H), 7.30 (d,
J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1,
146.5, 139.8, 137.0, 129.9, 129.4, 129.3, 128.7, 128.1, 128.0, 127.2, 126.7,
126.4, 116.9, 21.4; HR-MS calcd for C16H12BrN ([M + H]+) 298.0253,
found 298.0255.
gel (PE/EA, from 80/1 to 40/1); pale yellow solid; yield 88% (54.1 mg);
1
mp 73 °C; H NMR (300 MHz, CDCl3) δ 7.43−7.56 (m, 4H), 7.73
(t, J = 5.9 Hz, 1H), 7.78−7.88 (m, 2H), 8.13−8.23 (m, 4H).
2-(m-Tolyl)quinoline (2; Table 2):19 column chromatography, silica
gel (PE/EA, from 80/1 to 40/1); yellow solid; yield 92% (60.5 mg); mp
36 °C; 1H NMR (300 MHz, CDCl3) δ 8.19−8.15 (m, 2H), 8.00 (s, 1H),
7.91 (d, J = 7.7 Hz, 1H), 7.85−7.77 (m, 2H), 7.75−7.67 (m, 1H), 7.52−
7.47 (m, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30−7.21 (m, 1H), 2.47 (s, 3H).
2-(p-Tolyl)quinoline (3; Table 2):5b column chromatography, silica
gel (PE/EA, from 80/1 to 40/1); white solid; yield 93% (61.2 mg); mp
78 °C; 1H NMR (300 MHz, CDCl3) δ 8.18−8.13 (m, 2H), 8.06 (d, J =
8.0 Hz, 2H), 7.83−7.76 (m, 2H), 7.73−7.65 (m, 1H), 7.51−7.45
(m, 1H), 7.31 (d, J = 8.1 Hz, 2H), 2.41 (s, 3H).
3-Bromo-2-(p-tolyl)quinoline (16; Table 2):22 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); paleyellow solid; yield
96% (85.5 mg); mp 92 °C; 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H),
8.12 (d, J = 8.4 Hz, 1H), 7.75−7.64 (m, 4H), 7.52 (t, J = 7.6 Hz, 1H),
7.30 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H).
3-Bromo-2-(2-methoxyphenyl)quinoline (17; Table 2): column
chromatography, silica gel (PE/EA, from 80/1 to 20/1); white solid;
yield 95% (89.2 mg); mp 143 °C; 1H NMR (400 MHz, CDCl3) δ 8.49
(s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.79−7.72 (m, 2H), 7.59−7.55 (m,
1H), 7.44−7.39 (m, 1H), 7.32−7.24 (m, 2H), 7.04−6.96 (m, 1H), 3.87
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 158.0, 146.4, 139.9,
130.0, 129.8, 129.5, 129.1, 128.2, 127.4, 126.4, 121.8, 114.8, 114.7, 55.3;
HR-MS calcd for C16H12BrNO ([M − Br + H]+) 236.1070, found
236.1074.
3-Bromo-2-(3-methoxyphenyl)quinoline (18; Table 2): column
chromatography, silica gel (PE/EA, from 80/1 to 20/1); white solid;
yield 89% (83.6 mg); mp 136 °C; 1H NMR (400 MHz, CDCl3) δ 8.49
(s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.79−7.72 (m, 2H), 7.60−7.55 (m,
1H), 7.44−7.39 (m, 1H), 7.32−7.25 (m, 2H), 7.04−7.00 (m, 1H), 3.87
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 158.0, 146.4, 141.0,
140.0, 130.1, 129.5, 129.1, 128.2, 127.5, 126.4, 121.8, 116.8, 114.8, 114.7,
55.3; HR-MS calcd for C16H12BrNO ([M − Br + H]+) 236.1070, found
236.1075.
3-Bromo-2-(4-methoxyphenyl)quinoline (19; Table 2): column
chromatography, silica gel (PE/EA, from 80/1 to 20/1); white solid;
yield 90% (84.5 mg); mp 122 °C; 1H NMR (400 MHz, CDCl3) δ 8.45
(s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.76−7.69 (m, 4H), 7.55−7.51 (t, J =
7.6 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.1, 157.6, 146.5, 139.9, 132.2, 130.9, 129.9, 129.3, 127.9,
127.1, 126.3, 117.0, 113.3, 55.3; HR-MS calcd for C16H12BrNO ([M −
Br + H]+) 236.1070, found 236.1078.
2-(2-Methoxyphenyl)quinoline (4; Table 2):20 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 20/1); yellow solid; yield 92%
(65.2 mg); mp 59 °C; 1H NMR (300 MHz, CDCl3) δ 8.23−8.17 (m,
2H), 7.88−7.78 (m, 3H), 7.77−7.71 (m, 2H), 7.55−7.50 (m, 1H), 7.45
(t, J = 8.0 Hz, 1H), 7.05−7.01 (m, 1H), 3.94 (s, 3H).
2-(3-Methoxyphenyl)quinoline (5; Table 2):20 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 20/1); pale yellow oil; yield 79%
(55.7 mg); 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.13 (dd, J =
8.2, 1.0 Hz, 1H), 7.71 (m, 2H), 7.58−7.49 (m, 3H), 7.36 (m, 1H), 7.32−
7.12 (m, 2H), 2.43 (s, 3H).
2-(4-Methoxyphenyl)quinoline (6; Table 2):4d column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 20/1); white solid; yield 84%
(59.2 mg); mp 113 °C; 1H NMR (300 MHz, CDCl3) δ 8.21−8.11 (m,
4H), 7.82 (t, J = 8.7 Hz, 2H), 7.74−7.67 (m, 1H), 7.53−7.46 (m, 1H),
7.08−7.02 (m, 2H), 3.88 (s, 3H).
2-(Naphthalen-2-yl)quinoline (7; Table 2):5b,9a column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); white solid; yield 64%
(49.0 mg); mp 169 °C; 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 2H),
7.99−7.86 (m, 7H), 7.53−7.50 (m, 4H).
2-(3,5-Dimethylphenyl)quinoline (8; Table 2):5b column chroma-
tography, silica gel (PE/EA, from 80/1 to 40/1); colorless oil; yield 81%
(56.6 mg); 1H NMR (300 MHz, CDCl3) δ 8.23−8.11 (m, 2H), 7.87−
7.66 (m, 5H), 7.51−7.47 (m, 1H), 7.09 (s, 1H), 2.43 (s, 6H).
2-(4-Fluorophenyl)quinoline (9; Table 2):5b column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); white solid; yield 72%
(48.2 mg); mp 85 °C; 1H NMR (300 MHz, CDCl3) δ 8.25−8.09 (m,
4H), 7.83−7.75 (m, 2H), 7.75−7.67 (m, 1H), 7.50 (t, J = 7.5 Hz, 1H),
7.26−7.14 (m, 2H).
6-Methyl-2-phenylquinoline (20; Table 2):23 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); yellow solid; yield 76%
(50.1 mg); mp 66 °C; 1H NMR (400 MHz, CDCl3) δ 8.15−8.05 (m,
4H), 7.78 (d, J = 8.8 Hz, 1H), 7.55−7.43 (m, 5H), 2.52 (s, 3H).
6-Methyl-2-(m-tolyl)quinoline (21; Table 2):24 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); yellow solid; yield 79%
(55.3 mg); mp 76 °C; 1H NMR (400 MHz, CDCl3) δ 8.08−7.98 (m,
3H), 7.88 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.53 (s, 2H),
7.41−7.36 (m, 1H), 7.26−7.23 (m, 1H), 2.51 (s, 3H), 2.45 (s, 3H).
6-Methyl-2-(p-tolyl)quinoline (22; Table 2):25 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); yellow solid; yield 80%
(56.0 mg); mp 133 °C; 1H NMR (400 MHz, CDCl3) δ 8.10−8.03 (m,
4H), 7.80 (d, J = 8.4 Hz, 1H), 7.56−7.52 (m, 2H), 7.31 (d, J = 7.6 Hz,
2H), 2.53 (s, 3H), 2.42 (s, 3H).
2-(4-Chlorophenyl)quinoline (10; Table 2):4d,5b column chroma-
tography, silica gel (PE/EA, from 80/1 to 40/1); white solid; yield 50%
1
(35.9 mg); mp 107 °C; H NMR (300 MHz, CDCl3) δ 8.25−8.07
(m, 4H), 7.82 (d, J = 8.6 Hz, 2H), 7.76−7.70 (m, 1H), 7.57−7.45 (m, 3H).
2-(Benzofuran-5-yl)quinoline (11; Table 2): column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 20/1); white solid; yield 71%
(52.2 mg); mp 70 °C; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 1.7 Hz,
1H), 8.25−8.10 (m, 3H), 7.90 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.0 Hz,
1H), 7.77−7.68 (m, 1H), 7.67−7.61 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H),
6.86 (d, J = 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.6, 155.7,
148.2, 145.7, 136.7, 134.8, 129.6, 129.5, 128.0, 127.4, 126.9, 126.1, 124.2,
120.6, 119.1, 111.6, 107.1; HR-MS calcd for C17H11NO ([M + H]+)
246.0913, found 246.0916.
4-Methyl-2-phenylquinoline (23; Table 2):9b column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); yellow solid; yield 57%
(37.5 mg); mp 49 °C; 1H NMR (400 MHz, CDCl3) δ 8.19−8.12 (m,
3H), 7.95−7.92 (m, 1H), 7.71−7.66 (m, 2H), 7.52−7.40 (m, 4H), 2.70
(s, 3H).
2-(Thiophen-2-yl)quinoline (12; Table 2):20 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); white solid; yield 55%
8-Methyl-2-phenylquinoline (24; Table 2):23 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); yellow oil; yield 78% (51.3
mg); 1H NMR (400 MHz, CDCl3) δ 8.28−8.17 (m, 3H), 7.91 (d, J = 8.4
Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.58−7.39 (m, 5H), 2.91 (s, 3H).
1-Phenylisoquinoline (25; Table 3):4d,7b column chromatography,
silica gel (PE/EA, from 40/1 to 15/1); white solid; yield 60% (36.9 mg);
mp 79 °C; 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J = 5.7 Hz, 1H), 8.10
(d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.74−7.62 (m, 4H), 7.58−
7.47 (m, 4H).
1
(34.8 mg); mp 131 °C; H NMR (400 MHz, CDCl3) δ 8.12−8.08
(m, 2H), 7.79−7.66 (m, 4H), 7.49−7.45 (m, 2H), 7.25−7.13 (m, 1H).
2-(Benzo[b]thiophen-3-yl)quinoline (13; Table 2):21 column
chromatography, silica gel (PE/EA, from 80/1 to 40/1); yellow solid;
yield 88% (68.9 mg); mp 81 °C; 1H NMR (400 MHz, CDCl3) δ 8.10 (d,
J = 8.0 Hz, 1H), 8.24−8.17 (m, 2H), 7.94−7.71 (m, 5H), 7.55−7.32
(m, 3H).
3-Bromo-2-phenylquinoline (14; Table 2):22 column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); pale yellow solid; yield
95% (80.7 mg); mp 86 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H),
8.12 (d, J = 8.4 Hz, 1H), 7.77−7.71(m, 4H), 7.58−7.44 (m, 4H).
3-Bromo-2-(m-tolyl)quinoline (15; Table 2): column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); white solid; yield 96%
1-(p-Tolyl)isoquinoline (26; Table 3):4d column chromatography,
silica gel (PE/EA, from 40/1 to 15/1); yellow oil; yield 64% (42.1 mg);
1H NMR (300 MHz, CDCl3) δ 8.57 (d, J = 5.8 Hz, 1H), 8.13 (d, J = 8.5
Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.74−7.50 (m, 5H), 7.36−7.28
(m, 2H), 2.45 (s, 3H).
E
dx.doi.org/10.1021/jo400152f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1-(3,5-Dimethylphenyl)isoquinoline (27; Table 3):26 column
chromatography, silica gel (PE/EA, from 40/1 to 15/1); yellow solid;
yield 55% (38.5 mg); mp 26 °C; 1H NMR (300 MHz, CDCl3) δ 8.58 (d,
J = 5.7 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.73−
7.61 (m, 2H), 7.54 (dd, J = 11.3, 4.0 Hz, 1H), 7.30 (s, 2H), 7.13 (s, 1H),
2.40 (s, 6H).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are greatly thankful for financial support from the National
Natural Science Foundation of China (No. 21072087) and the
Program for Changjiang Scholars and Innovative Research Team
in University (IRT1137).
5-Bromo-1-phenylisoquinoline (28; Table 3): column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); white solid; yield 69%
(58.8 mg); mp 65 °C; 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J = 5.9 Hz,
1H), 8.13−7.93 (m, 3H), 7.72−7.61 (m, 2H), 7.59−7.49 (m, 3H),
7.42−7.34 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 161.1, 143.7, 143.3,
135.9, 133.8, 133.7, 129.9, 128.7, 128.3, 127.8, 127.3, 121.9, 118.8; HR-
MS calcd for C15H10BrN ([M + H]+) 284.0069, found 284.0075.
5-Bromo-1-(m-tolyl)isoquinoline (29; Table 3): column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); white solid; yield 65%
(57.8 mg); mp 56 °C; 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J = 5.9 Hz,
1H), 8.12−7.94 (m, 3H), 7.52−7.29 (m, 5H), 2.46 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 161.4, 143.6, 143.3, 139.0, 138.2, 135.9, 133.8,
130.5, 129.5, 128.1, 127.9, 127.6, 127.3, 127.0, 121.9, 118.7, 21.5; HR-
MS calcd for C16H12BrN ([M + H]+) 298.0226, found 298.0232.
5-Bromo-1-(p-tolyl)isoquinoline (30; Table 3): column chromatog-
raphy, silica gel (PE/EA, from 80/1 to 40/1); white solid; yield 71%
(63.5 mg); mp 84 °C; 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J = 5.9 Hz,
1H), 8.11−8.08 (m, 1H), 8.00−7.94 (m, 2H), 7.56 (d, J = 8.1 Hz, 2H),
7.39−7.30 (m, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.2,
143.4, 138.7, 136.2, 135.9, 133.6, 129.9, 129.0, 127.9, 127.6, 127.2, 121.9,
118.4, 21.3; HR-MS calcd for C16H12BrN ([M + H]+) 298.0226, found
298.0229.
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2-Methyl-5-phenylpyridine (32; Scheme 1):7b column chromatog-
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mg); 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.4 Hz, 1H), 7.62−7.37
(m, 6H), 7.22−7.13 (m, 1H), 2.36 (s, 3H).
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7.96−7.92 (m, 3H), 7.77 (d, J = 8.4 Hz, 1H), 7.64−7.61 (m, 2H), 7.51−
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ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving NMR spectra of the compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail for C.-S.D.: dachaoshan@lzu.edu.cn.
F
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