A microwave-assisted domino benzannulation reaction towards functionalized naphthalenes, quinolines, and isoquinolines

Article abstract of DOI:10.1002/ejoc.201201061

An efficient palladium/copper-catalyzed domino reaction was developed to yield functionalized naphthalenes, quinolines, and isoquinolines. The reactions of various substituted 1-phenylprop-2-yn-1-ols containing electron-donating (EDG) and electron-withdrawing (EWG) groups and 1-heteroarylprop-2-yn-1-ols worked well with this procedure. Both electron-rich and-deficient aryl halides were satisfactory substrates for this reaction. This domino benzannulation process involves a Sonogashira cross-coupling reaction, followed by isomerization to a chalcone, and finally an intramolecular condensation reaction.

Full text of DOI:10.1002/ejoc.201201061

FULL PAPER
DOI: 10.1002/ejoc.201201061
A Microwave-Assisted Domino Benzannulation Reaction towards
Functionalized Naphthalenes, Quinolines, and Isoquinolines
Yuqin Wang,[a] Cun Tan,[a] Xiaofei Zhang,[a] Qian He,[a] Yuyuan Xie,[a] and
Chunhao Yang*[a]
Keywords: Synthetic methods / Domino reactions / Cross-coupling / Isomerization / Nitrogen heterocycles
An efficient palladium/copper-catalyzed domino reaction
was developed to yield functionalized naphthalenes, quinol-
ines, and isoquinolines. The reactions of various substituted
1-phenylprop-2-yn-1-ols containing electron-donating (EDG)
and electron-withdrawing (EWG) groups and 1-heteroaryl-
prop-2-yn-1-ols worked well with this procedure. Both elec-
tron-rich and -deficient aryl halides were satisfactory sub-
strates for this reaction. This domino benzannulation process
involves a Sonogashira cross-coupling reaction, followed by
isomerization to a chalcone, and finally an intramolecular
condensation reaction.
Introduction
arylpropargyl alcohols to furnish 1,3-diarylpropenones (see
Scheme 1, reaction a).[13] This route proceeded through a
Sonogashira coupling reaction followed by a base-catalyzed
isomerization from the propargyl alcohol to the enone.
Naphthalenes, quinolines, and isoquinolines are impor-
tant scaffolds, which are widely used in biological and me-
dicinal chemistry[1] as well as synthetic chemistry.[2] Substi-
tuted naphthalene and its aza analogues are attractive as
NK1 receptor antagonists,[3] antibacterial agents,[4] 17β-
HSD1/2 inhibitors,[5] antitumor agents,[6] antimalarials,[7]
antitumor antibiotics,[8] Rho-kinase inhibitors,[9] and as ag-
rochemicals. Furthermore, they are interesting synthetic
blocks in organic reactions. Because of their prevalence in
active compounds, a number of synthetic methods have
been developed to construct these structural units.[1d,10]
Among these methods, transition-metal-catalyzed cross-
coupling reactions have been the most powerful tools, using
the readily available naphthalene, quinoline, and isoquin-
oline building blocks.[11] However, the development of new
synthetic strategies, which are effective and versatile, re-
mains an ever-present challenge.
Scheme 1. (a) Coupling–isomerization reaction (CIR) between aryl
halides and arylpropargyl alcohols. (b) This work.
Subsequently, a series of pharmaceutically relevant het-
erocycles, such as pyrazolines,[13] pyrimidines,[14] 1,5-benzo-
heteroazepines,[15] pyrroles,[16] pyridines,[17] tetrahydroquin-
olines,[17] annelated 2-aminopyridines,[18] and 2-arylquinol-
ines,[7a] have been synthesized by using this palladium/cop-
per-catalyzed domino cross-coupling–isomerization se-
quence. We predicted that o-halo-substituted phenylacetoni-
triles would react with arylpropargyl alcohols followed by
a condensation reaction to furnish substituted naphthalenes
through a one-pot cascade reaction sequence (see Scheme 1,
reaction b). Therefore, we set out to develop a new and
straightforward domino reaction with 2-(2-iodophenyl)-
acetonitrile and 1-phenylprop-2-yn-1-ol as the starting ma-
terials to prepare the naphthalenes in a one-pot synthesis.
To the best of our knowledge, the benzannulation reac-
tion applied to the syntheses of aryl-substituted naphth-
alenes and quinolines has not been adequately explored.[12]
In 2000, Müller et al. reported on a coupling–isomerization
reaction (CIR) between electron-deficient aryl halides and
[a] State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica,
555 Zu Chong Zhi Road, Shanghai 201203, P. R. China
Fax: +86-21-50806770
E-mail: chyang@mail.shcnc.ac.cn
Homepage: http://sourcedb.cas.cn/sourcedb_simm_cas/yw/
zjrcyw/201111/t20111122_3399860.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201061.
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A Microwave-Assisted Domino Benzannulation Reaction
Table 2. Domino reaction of 2-(2-halophenyl)acetonitrile with sub-
stituted 1-arylprop-2-yn-1-ols.[a]
Results and Discussion
In 2006, Müller reported on a microwave-accelerated
coupling–isomerization reaction (MACIR) to yield enones
rapidly.[18] We conducted the reaction in a similar manner
to Müller’s approach.
As anticipated, this protocol yielded the desired com-
pound 2-phenyl-1-naphthonitrile in 84% yield by using
Pd(PPh3)2Cl2 as a catalyst (see Table 1, Entry 1). Other Pd
catalysts were less effective (see Table 1, Entries 2, 3, 4, and
5), resulting in lower yields. In addition, the yield decreased
greatly by reducing the amount of DBU (1,8-diazabicy-
clo[5.4.0]undec-7-ene) to 1 equiv. (see Table 1, Entry 6). In-
creasing the amount of DBU to 3 equiv. also lowered the
yield to 70% (see Table 1, Entry 7). When the reaction was
conducted at 120 and 80 °C, similar results were obtained
(see Table 1, Entries 9 and 10). Among the screened bases,
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) was
as effective as DBU (see Table 1, Entry 12). However, no
product was obtained using Et3N or the inorganic base
K2CO3 (see Table 1, Entries 13 and 14). DBU was eventu-
ally selected as the base for our approach, as it is easily
available and much cheaper than MTBD. Different solvents
were further screened, and toluene afforded better results
than dioxane and CH3CN. When the reaction was con-
Table 1. Optimization of reaction conditions.[a]
Entry Pd catalyst
Base [equiv.] Solvent
Temp. [°C] % Yield[b]
1
2
3
4
5
6
7
Pd(PPh3)2Cl2
Pd(dppf)Cl2
Pd2(dba)3
Pd(CH3CN)2Cl2 DBU (2)
Pd(PPh3)4
DBU (2)
DBU (2)
DBU (2)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
100
100
100
100
100
100
100
100
120
80
100
100
100
100
100
100
100
100
84
66
67
69
69
36
70
52
68
71
60
85
0
DBU (2)
DBU (1)
DBU (3)
DBU (2)
DBU (2)
DBU (2)
DBN (2)
MTBD (2) THF
Et3N (2) THF
K2CO3 (2) THF
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
8[c]
9
10
11
12
13
14
15
16
17
18[d]
0
DBU (2)
DBU (2)
DBU (2)
DBU (2)
toluene
83
78
76
75
dioxane
CH3CN
THF
[a] Reagent and conditions: 1a (122 mg, 0.5 mmol), 2a (66 mg,
0.5 mmol), solvent (3 mL), MW (microwave), 30 min. [b] Isolated
yield. [c] No PPh3 was added to reaction mixture. [d] The reaction
was heated in an oil bath for 3 h.
[a] Reagents and conditions: 1a (122 mg, 0.5 mmol), 2a–2n
(0.5 mmol), Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), CuI (1 mg,
0.005 mmol), PPh3 (26 mg, 0.1 mmol), solvent (3 mL), MW,
30 min. [b] Isolated yield. [c] Reaction time was 3 h.
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Y. Wang, C. Tan, X. Zhang, Q. He, Y. Xie, C. Yang
FULL PAPER
ducted under conventional heating in THF (tetra- with electron-donating groups in the meta position, very
hydrofuran) for 3 h, 3a was obtained in 75% yield (see good yields were obtained (see Table 2, Entries 3 and 6).
Table 1, Entry 18).
However, propargyl alcohols substituted by aryl groups
Using the optimized reaction conditions [2 mol-% equiv. with electron-donating groups in the ortho and para posi-
Pd(PPh3)2Cl2, 1 mol-% equiv. CuI, 20 mol-% equiv. PPh3, tions needed prolonged reaction times to achieve good
THF, 100 °C], we next explored the scope and generality yields. This is presumably because the electron-donating
of this palladium/copper-catalyzed domino cross-coupling groups did not favor the isomerization step in this domino
isomerization–condensation reaction.
reaction sequence. Electron-withdrawing group substi-
As shown in Table 2, various 1-arylprop-2-yn-1-ols were tutents (such as CF3) at the meta and para positions of the
tested in this method. The electronic nature of the propar- aryl group gave moderate yields (see Table 2, Entries 9 and
gyl alcohols plays an important role in this transformation. 10), whereas substitution at ortho position afforded a good
When propargyl alcohols were substituted by aryl groups yield (see Table 2, Entry 8). With the 1-heteroarylprop-2-
yn-1-ols, excellent yields were obtained using 1-(thiophen-
3-yl)prop-2-yn-1-ol and 1-(pyridin-3-yl)prop-2-yn-1-ol (see
Table 2, Entries 13 and 14). However, only moderate yields
of the products were obtained with 1-(furan-2-yl)prop-2-yn-
1-ol and 1-(thiophen-2-yl)prop-2-yn-1-ol (see Table 2, En-
tries 11 and 12). Subsequently, the reaction was performed
under the standard conditions using the less active 2-(2-
bromophenyl)acetonitrile with 1-phenylprop-2-yn-1-ol, re-
sulting in 72% yield of the product (see Table 2, Entry 16),
which was a lower yield than that of the same reaction with
2-(2-iodophenyl)acetonitrile. Furthermore, under these re-
action conditions, the electron-rich 2-(2-iodo-4,5-dimeth-
oxyphenyl)acetonitrile also gave an acceptable yield (see
Table 2, Entry 15). Using this CIR procedure, the reactions
went smoothly with the electron-deficient 2-(2-chloropyr-
idin-3-yl)acetonitrile and various 1-arylprop-2-yn-1-ols as
shown in Table 3. Both electron-rich and -deficient aryl
alcohols exhibited similar reaction activity as those shown
in Table 2.
Table 3. Reaction of 2-(2-chloropyridin-3-yl)acetonitrile and substi-
tuted 1-arylprop-2-yn-1-ols.[a]
Additionally, methyl 2-(2-iodophenyl)acetate (1e) was
further explored using this method (see Scheme 2). With the
exception of 5c, this protocol resulted in a decreased yield
of the products compared to that of 1a. This could be ex-
plained by the fact that the electron-withdrawing ability of
the ester group is weaker than that of nitrile group, which
would make the condensation step slower and, therefore,
result in lower yields.
Scheme 2. Reaction of methyl 2-(2-iodophenyl)acetate with substi-
tuted 1-arylprop-2-yn-1-ols.
[a] Reagents and conditions: 1d (76 mg, 0.5 mmol), 2 (0.5 mmol),
Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), CuI (1 mg, 0.005 mmol), PPh3
(26 mg, 0.1 mmol), solvent (3 mL), MW, 30 min. [b] Isolated yield.
[c] Reaction time was 3 h.
Furthermore, the electron-deficient heteroaryl halides 1f
and 1g were tested under this protocol (Scheme 3). 6-Phen-
ylisoquinoline (5d) and 7-phenylquinoline (5e) were ob-
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A Microwave-Assisted Domino Benzannulation Reaction
Scheme 3. Reaction of electron-deficient heteroaryl halides with substituted 1-phenylprop-2-yn-1-ol.
removed in vacuo, and the crude product was eluted on silica gel
with petroleum ether/ethyl acetate to give the corresponding prod-
ucts.
tained with acceptable yields. These results suggest that this
useful methodology could easily be used to achieve struc-
tural diversity.
2-Phenyl-1-naphthonitrile (3a): Light yellow powder; m.p. 120–
1
121 °C; ref.[20] m.p. 119 °C. H NMR (300 MHz, CDCl3): δ = 8.36
(d, J = 8.0 Hz, 1 H), 8.11 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.1 Hz,
1 H), 7.74 (td, J = 8.4, 1.3 Hz, 1 H), 7.70–7.60 (m, 4 H), 7.57–7.49
(m, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 145.89, 138.64,
133.12, 132.95 (CH), 131.81, 129.21 (CH), 128.96 (CH), 128.90
(CH), 128.79 (CH), 128.46 (CH), 127.38 (CH), 127.18 (CH), 125.68
(CH), 117.56, 108.08 ppm.
2-(o-Tolyl)-1-naphthonitrile (3b): Light yellow oil. 1H NMR
(500 MHz, CDCl3): δ = 8.33 (d, J = 8.3 Hz, 1 H), 8.10 (d, J =
8.4 Hz, 1 H), 7.98 (d, J = 8.2 Hz, 1 H), 7.75 (td, J = 8.1, 1.0 Hz, 1
H), 7.66 (td, J = 8.1, 1.0 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.41–
7.30 (m, 4 H), 2.24 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 146.46, 138.52, 135.77, 132.72, 132.51 (CH), 131.82, 130.53
(CH), 129.56 (CH), 128.90 (CH), 128.53 (CH), 127.53 (CH), 127.39
(CH), 125.96 (CH), 125.50 (CH), 116.96, 109.75, 20.02 (CH3) ppm.
MS (EI): m/z (%) = 243 (65) [M]+, 242 (100). HRMS (EI): calcd.
for C18H13N 243.1048; found 243.1048.
Conclusions
By using a facile one-pot procedure under mild condi-
tions, we have developed a versatile palladium/copper-cata-
lyzed domino cross-coupling–isomerization–condensation
sequence to access functionalized naphthalenes, quinolones,
and isoquinolines. The reaction went smoothly with both
electron-rich and -deficient aryl halides. This protocol has
a broad group tolerance with propargyl alcohols. Further
studies directed at taking advantage of this methodology
with other heterocyclic syntheses are currently under pro-
gress.
Experimental Section
2-(m-Tolyl)-1-naphthonitrile (3c): White powder; m.p. 89–90 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 8.4 Hz, 1 H), 8.10 (d,
J = 8.6 Hz, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 7.73 (td, J = 8.3, 1.2 Hz,
1 H), 7.66–7.59 (m, 2 H), 7.52–7.47 (m, 2 H), 7.43 (t, J = 8.0 Hz,
1 H), 7.31 (d, J = 8.0 Hz 1 H), 2.47 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 146.07, 138.62, 138.48, 133.12, 132.85
(CH), 131.78, 129.86 (CH), 129.65 (CH), 128.91 (CH), 128.68
(CH), 128.45 (CH), 127.30 (CH), 127.22 (CH), 126.32 (CH), 125.66
(CH), 117.58, 108.02, 21.52 (CH3) ppm. MS (EI): m/z (%) = 243
(65) [M]+, 242 (100). HRMS (EI): calcd. for C18H13N 243.1048;
found 243.1056.
General Information: All of the reagents, with the exception of 1a,
were commercially available products that were used without fur-
ther purification. Analytical thin-layer chromatography was per-
formed using HSGF 254 (0.15–0.2 mm thickness, Yantai Huiyou
Company, China). Column chromatography was carried out on sil-
1
ica gel (200–300 mesh). H and 13C NMR spectroscopic data were
recorded with Varian Mercury-400 and Varian Mercury-500 spec-
trometers. Tetramethylsilane was used as an internal standard. The
chemical shifts were reported in parts per million (ppm, δ). Proton
coupling patterns are described as singlet (s), doublet (d), triplet
(t), quartet (q), mutiplet (m), and broad (br.). Low and high resolu-
tion mass spectra were recorded with a Finnigan/MAT-95 spec-
trometer. Melting points were measured with a Büchi 510 melting
point apparatus. The microwave reaction was performed with a
CEM microwave reactor.
2-(p-Tolyl)-1-naphthonitrile (3d): White crystalline solid; m.p. 151–
1
152 °C; ref.[21] m.p. 147–150 °C. H NMR (400 MHz, CDCl3): δ =
8.34 (d, J = 8.5 Hz, 1 H), 8.08 (d, J = 8.6 Hz, 1 H), 7.93 (d, J =
8.2 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.63–7.57 (m, 4 H), 7.35 (d,
J = 7.9 Hz, 2 H), 2.45 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 145.95, 138.96, 135.75, 133.16, 132.88 (CH), 131.71, 129.52 (2
CH), 129.09 (2 CH), 128.88 (CH), 128.44 (CH), 127.24 (CH),
127.20 (CH), 125.62 (CH), 117.74, 107.86, 21.34 (CH3) ppm.
Ethyl 2-(3-Bromopyridin-4-yl)acetate (1f) and Ethyl 2-(3-Bromopyr-
idin-2-yl)acetate (1g): Compound 1f and 1g were prepared accord-
ing to the procedure described in ref.[19]
General Procedure for the Synthesis of Substituted Naphthalenes,
Quinolines, and Isoquinolines: To the mixture of aryl halides
(0.5 mmol), arylpropargyl alcohols (0.5 mmol), Pd(PPh3)2Cl2
(7 mg, 0.01 mmol), CuI (1 mg, 0.005 mmol), and PPh3 (26 mg,
0.1 mmol) in anhydrous THF (3 mL) was added DBU (0.15 mL)
under nitrogen. Then, the reaction was performed in a microwave
reactor at 100 °C. When the reaction was complete, the solvent was
1
2-(2-Methoxyphenyl)-1-naphthonitrile (3e): Colorless oil. H NMR
(400 MHz, CDCl3): δ = 8.33 (dd, J = 8.1, 1.0 Hz, 1 H), 8.08 (d, J
= 8.5 Hz, 1 H), 7.94 (d, J = 8.2 Hz, 1 H), 7.71 (td, J = 7.6, 1.3 Hz,
1 H), 7.62 (td, J = 7.5, 1.2 Hz, 1 H), 7.57 (d, J = 8.5 Hz, 1 H), 7.46
(ddd, J = 9.2, 7.8, 1.6 Hz, 1 H), 7.39 (dd, J = 7.5, 1.5 Hz, 1 H),
7.11–7.06 (m, 2 H), 3.85 (s, 3 H) ppm. 13C NMR (125 MHz,
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Y. Wang, C. Tan, X. Zhang, Q. He, Y. Xie, C. Yang
FULL PAPER
CDCl3): δ = 156.58, 143.14, 132.83, 132.21 (CH), 131.84, 131.20
3.5, 1.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 150.24,
(CH), 130.51 (CH), 128.58 (CH), 128.40 (CH), 128.19 (CH), 143.82 (CH), 133.31, 133.21, 133.05 (CH), 131.60, 129.02 (CH),
127.66, 127.20 (CH), 125.55 (CH), 120.84 (CH), 117.39, 111.42 128.42 (CH), 127.27 (CH), 125.51 (CH), 122.95 (CH), 117.86,
(CH), 110.07, 55.54 (CH3) ppm. MS (EI): m/z (%) = 259 (100)
112.59 (CH), 111.82 (CH), 102.97 ppm. MS (EI): m/z (%) = 219
(100) [M]+. HRMS (EI): calcd. for C15H9NO 219.0684; found
219.0684.
[M]+. HRMS (EI): calcd. for C18H13NO 259.0997; found 259.0990.
2-(3-Methoxyphenyl)-1-naphthonitrile (3f): White powder; m.p. 99–
100 °C; ref.[22] m.p. 97–98 °C. 1H NMR (300 MHz, CDCl3): δ = 2-(Thiophen-2-yl)-1-naphthonitrile (3l): White powder; m.p. 87–
8.36 (d, J = 8.4 Hz, 1 H), 8.10 (d, J = 8.6 Hz, 1 H), 7.95 (d, J = 88 °C. 1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 8.4 Hz, 1 H),
8.1 Hz, 1 H), 7.73 (dd, J = 11.2, 4.1 Hz, 1 H), 7.63 (t, J = 7.9 Hz,
2 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.27–7.20 (m, 2 H), 7.03 (dd, J =
8.3, 2.5 Hz, 1 H), 3.90 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
8.04 (d, J = 8.5 Hz, 1 H), 7.90 (dd, J = 8.1, 0.5 Hz, 1 H), 7.82 (dd,
J = 4.6, 1.2 Hz, 1 H), 7.74–7.69 (m, 2 H), 7.60 (ddd, J = 8.1, 7.0,
1.1 Hz, 1 H), 7.52 (dd, J = 4.6, 1.2 Hz, 1 H), 7.22 (q, J = 4.7 Hz, 1
δ = 159.71, 145.72, 139.94, 133.09, 132.92, 131.87, 129.86, 128.97, H) ppm. 13C NMR (125 MHz, CDCl3): δ = 140.06, 137.81, 133.38,
128.46, 127.40, 127.10, 125.69, 121.61, 117.49, 114.72, 114.66,
133.12 (CH), 131.77, 129.18 (CH), 128.51 (CH), 128.45 (CH),
128.39 (CH), 128.11 (CH), 127.45 (CH), 126.78 (CH), 125.72 (CH),
117.80, 106.37 ppm. MS (EI): m/z (%) = 235 (100) [M]+. HRMS
(EI): calcd. for C15H9NS 235.0456; found 235.0451.
108.10, 55.45 ppm. MS (EI): m/z (%) = 259 (100) [M]+.
2-(4-Methoxyphenyl)-1-naphthonitrile (3g): White powder; m.p.
134–135 °C; ref.[21] m.p. 133.5–136.5 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.34 (d, J = 8.4 Hz, 1 H), 8.07 (d, J = 8.6 Hz, 1 H),
7.93 (d, J = 8.3 Hz, 1 H), 7.71 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H),
7.66–7.57 (m, 4 H), 7.07 (dt, J = 8.9, 2.1 Hz, 2 H), 3.90 (d, J =
2-(Thiophen-3-yl)-1-naphthonitrile (3m): White powder; m.p. 97–
1
98 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.31 (d, J = 8.6 Hz,
1 H), 8.16 (d, J = 8.4 Hz, 1 H), 8.11 (d, J = 8.5 Hz, 2 H), 7.84–
4.2 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 160.24, 7.76 (m, 3 H), 7.69 (t, J = 7.3 Hz, 1 H), 7.63 (dd, J = 5.0, 0.9 Hz,
145.61, 133.22, 132.87 (CH), 131.58, 130.94, 130.52 (2 C, CH),
1 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 140.14, 138.91,
128.88 (CH), 128.42 (CH), 127.18 (CH), 127.14 (CH), 125.57 (CH), 134.04 (CH), 132.81, 131.85, 130.00 (CH), 129.32 (CH), 128.50
117.87, 114.28 (2 C, CH), 107.55, 55.41 (CH3) ppm. MS (EI): m/z (CH), 128.00 (CH), 127.89 (CH), 127.44 (CH), 127.05 (CH), 125.01
(%) = 259 (100) [M]+.
(CH), 117.98, 106.08 ppm. MS (EI): m/z (%) = 235 (100) [M]+.
HRMS (EI): calcd. for C15H9NS 235.0456; found 235.0454.
2-[2-(Trifluoromethyl)phenyl]-1-naphthonitrile (3h): White powder;
m.p. 97–99 °C. 1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J =
2-(Pyridin-3-yl)-1-naphthonitrile (3n): White powder; m.p. 157–
1
8.4 Hz, 1 H), 8.08 (d, J = 8.5 Hz, 1 H), 7.98 (d, J = 8.2 Hz, 1 H), 158 °C. H NMR (400 MHz, CDCl3): δ = 8.90 (s, 1 H), 8.75 (s, 1
7.85 (d, J = 8.2 Hz, 1 H), 7.75 (td, J = 7.8, 1.2 Hz, 1 H), 7.70–7.76 H), 8.35 (dd, J = 8.4, 0.8 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 8.06
(m, 2 H), 7.61 (t, J = 7.7 Hz, 1 H), 7.49 (d, J = 8.5 Hz, 1 H), 7.44 (dt, J = 8.1, 1.6 Hz, 1 H), 7.98 (d, J = 8.2 Hz, 1 H), 7.76 (ddd, J
(d, J = 7.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
143.71, 139.82, 137.44, 132.28, 132.15, 131.94 (CH), 131.78 (CH),
= 8.2, 7.0, 1.3 Hz, 1 H), 7.67 (ddd, J = 8.1, 7.0, 1.2 Hz, 1 H), 7.60
(d, J = 8.5 Hz, 1 H), 7.49 (dd, J = 7.7, 4.9 Hz, 1 H) ppm. 13C NMR
131.59 (CH), 129.90, 129.09 (CH), 129.06 (CH), 128.68, 128.57 (125 MHz, CDCl3): δ = 149.93 (CH), 149.67 (CH), 142.10, 136.50
(CH), 127.78 (CH), 127.13 (CH), 126.46 (q, J = 3.8 Hz, CH-C-
CF3), 125.58 (CH), 123.78 (d, J = 274.5 Hz, CF3), 122.69, 116.42,
110.24 ppm. MS (EI): m/z (%) = 297 (100) [M]+. HRMS (EI):
calcd. for C18H11F3N 297.0765; found 297.0773.
(CH), 134.60, 133.41 (CH), 133.05, 132.13, 129.31 (CH), 128.56
(CH), 127.89 (CH), 126.61 (CH), 125.68 (CH), 123.53 (CH),
117.07, 108.73 ppm. MS (EI): m/z (%) = 230 (100) [M]+. HRMS
(EI): calcd. for C16H10N2 230.0844; found 230.0850.
2-[3-(Trifluoromethyl)phenyl]-1-naphthonitrile (3i): Light yellow
powder; m.p. 92–94 °C; ref.[22] m.p. 94–95 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.36 (dd, J = 8.4, 0.8 Hz, 1 H), 8.15 (d, J = 8.5 Hz, 1
6,7-Dimethoxy-2-(m-tolyl)-1-naphthonitrile (3o): White powder;
m.p. 218–220 °C. 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J =
8.3 Hz, 1 H), 7.57 (s, 1 H), 7.47–7.38 (m, 4 H), 7.29–7.26 (m, 1 H),
H), 7.97 (d, J = 8.2 Hz, 1 H), 7.92–7.86 (m, 2 H), 7.79–7.74 (m, 2 7.18 (s, 1 H), 4.09 (s, 3 H), 4.04 (s, 3 H), 2.46 (s, 3 H) ppm. 13C
H), 7.70–7.64 (m, 2 H), 7.60 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 144.13, 139.38, 133.31 (CH), 133.00, 132.59
NMR (101 MHz, CDCl3): δ = 151.88, 150.31, 143.92, 138.91,
138.29, 130.96 (CH), 129.76 (CH), 129.65, 129.26 (CH), 128.51
(CH), 132.09, 131.44, 131.18, 129.35 (CH), 129.28 (CH), 128.54 (CH), 127.66, 126.18 (CH), 125.36 (CH), 118.06, 106.55 (CH),
(CH), 127.84 (CH), 126.72 (CH), 126.03 (q, J = 3.7 Hz, CH), 106.20, 104.17 (CH), 56.21 (CH3), 56.03 (CH3), 21.47 (CH3) ppm.
125.74 (CH), 125.63 (q, J = 3.7 Hz, CH), 123.92 (d, J = 273.0 Hz, MS (EI): m/z (%) = 303 (100) [M]+. HRMS (EI): calcd. for
CF3) 117.10, 108.52 ppm. MS (EI): m/z (%) = 297 (100) [M]+.
C20H7N2O2 303.1259; found 303.1259.
2-[4-(Trifluoromethyl)phenyl]-1-naphthonitrile (3j): White crystalline
solid; m.p. 100–101 °C; ref.[22] m.p. 91–93 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.37 (d, J = 8.4 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H),
7.98 (d, J = 8.1 Hz, 1 H), 7.83–7.78 (m, 4 H), 7.77 (t, J = 7.5 Hz,
1 H), 7.68 (t, J = 7.5 Hz, 1 H), 7.60 (d, J = 8.5 Hz, 1 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 145.57, 143.54, 134.68 (CH), 134.38,
133.52, 132.32 (d, J = 33 Hz, C-C-F3), 131.02 (2 CH), 130.69 (CH),
129.93 (CH), 129.26 (CH), 128.06 (CH), 127.23–127.01 (m, 3 CH),
125.40 (d, J = 271 Hz, CF3), 118.52, 109.86 ppm. MS (EI): m/z (%)
= 297 (100) [M]+.
6-Phenylquinoline-5-carbonitrile (4a): White powder; m.p. 140–
142 °C. 1H NMR (400 MHz, CDCl3): δ = 9.04 (dd, J = 4.2, 1.6 Hz,
1 H), 8.65 (ddd, J = 8.5, 1.6, 0.9 Hz, 1 H), 8.37 (dd, J = 8.8, 0.8 Hz,
1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.71–7.67 (m, 2 H), 7.65 (dd, J =
8.5, 4.2 Hz, 1 H), 7.58–7.50 (m, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 151.64 (CH), 146.62, 146.39, 137.84, 134.68 (CH),
133.84 (CH), 130.90 (CH), 129.31 (CH), 129.15 (2 CH), 128.96 (2
CH), 128.66, 123.53 (CH), 116.55, 108.08 ppm. MS (EI): m/z (%) =
230 (100) [M]+. HRMS (EI): calcd. for C16H10N2 230.0844; found
230.0842.
2-(Furan-2-yl)-1-naphthonitrile (3k): Light brown powder; m.p. 6-(o-Tolyl)quinoline-5-carbonitrile (4b): White powder; m.p. 134–
154–155 °C. 1H NMR (400 MHz, CDCl3): δ = 8.29 (dd, J = 8.3, 135 °C. 1H NMR (400 MHz, CDCl3): δ = 9.06 (dd, J = 4.2, 1.6 Hz,
3.5 Hz, 1 H), 8.05–7.95 (m, 2 H), 7.86 (dd, J = 8.0, 3.3 Hz, 1 H), 1 H), 8.61 (d, J = 8.5 Hz, 1 H), 8.36 (d, J = 8.7 Hz, 1 H), 7.71 (d,
7.68 (ddd, J = 8.5, 5.4, 2.3 Hz, 1 H), 7.63 (d, J = 1.6 Hz, 1 H), 7.56
(ddd, J = 8.9, 7.1, 2.2 Hz, 1 H), 7.52–7.46 (m, 1 H), 6.62 (dd, J =
J = 8.7 Hz, 1 H), 7.65 (dd, J = 8.5, 4.2 Hz, 1 H), 7.43–7.30 (m, 4
H), 2.23 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 151.65
6626
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A Microwave-Assisted Domino Benzannulation Reaction
(CH), 146.98, 146.52, 137.66, 135.61, 134.15 (CH), 133.60 (CH),
8.9 Hz, 1 H), 7.95 (d, J = 8.9 Hz, 1 H), 7.85 (dd, J = 3.7, 1.1 Hz,
131.23 (CH), 130.61 (CH), 129.44 (CH), 129.16 (CH), 128.19, 1 H), 7.62 (dd, J = 8.5, 4.2 Hz, 1 H), 7.55 (dd, J = 5.1, 1.1 Hz, 1
126.03 (CH), 123.42 (CH), 115.90, 109.77, 19.97 (CH3) ppm. MS
(EI): m/z (%) = 244 (100) [M]+. HRMS (EI): calcd. for C17H12N2
244.1000; found 244.0998.
H), 7.23 (dd, J = 5.1, 3.8 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 151.56 (CH), 146.56, 139.24, 138.32, 134.88 (CH),
133.77 (CH), 130.38 (CH), 129.01, 128.96 (CH), 128.81 (CH),
128.59 (CH), 123.71 (CH), 116.83, 106.02 ppm. MS (EI): m/z (%) =
236 (100) [M]+. HRMS (EI): calcd. for C14H8N2S 236.0408; found
236.0409.
6-(m-Tolyl)quinoline-5-carbonitrile (4c): Yellowish powder; m.p.
118–119 °C. 1H NMR (400 MHz, CDCl3): δ = 9.03 (dd, J = 4.2,
1.6 Hz, 1 H), 8.64 (ddd, J = 8.5, 1.6, 0.9 Hz, 1 H), 8.35 (dd, J =
8.8, 0.8 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.64 (dd, J = 8.5,
4.2 Hz, 1 H), 7.51–7.42 (m, 3 H), 7.32 (d, J = 7.6 Hz, 1 H), 2.47 (s,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 151.57 (CH), 146.61,
6-(Thiophen-3-yl)quinoline-5-carbonitrile (4i): Light yellow powder;
1
m.p. 204–205 °C. H NMR (400 MHz, CDCl3): δ = 9.00 (dd, J =
4.2, 1.5 Hz, 1 H), 8.60 (d, J = 8.4 Hz, 1 H), 8.32 (d, J = 8.9 Hz, 1
146.57, 138.71, 137.82, 134.60 (CH), 133.80 (CH), 130.94 (CH), H), 7.90 (d, J = 8.9 Hz, 1 H), 7.85 (dd, J = 2.9, 1.4 Hz, 1 H), 7.61
130.05 (CH), 129.80 (CH), 128.85 (CH), 128.65, 126.27 (CH), (dd, J = 8.5, 4.2 Hz, 1 H), 7.56 (dd, J = 5.0, 1.3 Hz, 1 H), 7.50 (dd,
123.49 (CH), 116.58, 108.00, 21.52 (CH3) ppm. MS (EI): m/z (%) =
244 (100) [M]+. HRMS (EI): calcd. for C17H12N2 244.1000; found
244.0998.
J = 5.0, 2.9 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
151.51 (CH), 146.56, 140.44, 138.19, 134.82 (CH), 133.73 (CH),
130.36 (CH), 128.83, 127.77 (CH), 126.95 (CH), 126.15 (CH),
123.56 (CH), 116.89, 106.86 ppm. MS (EI): m/z (%) = 236 (100)
[M]+. HRMS (EI): calcd. for C14H8N2S 236.0408; found 236.0399.
6-(p-Tolyl)quinoline-5-carbonitrile (4d): White powder; m.p. 129–
130 °C. 1H NMR (400 MHz, CDCl3): δ = 9.02 (dd, J = 4.2, 1.6 Hz,
1 H), 8.63 (ddd, J = 8.5, 1.6, 0.9 Hz, 1 H), 8.35 (dd, J = 8.8, 0.7 Hz,
1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.63 (dd, J = 8.5, 4.2 Hz, 1 H),
7.61–7.57 (m, 2 H), 7.36 (d, J = 7.8 Hz, 2 H), 2.45 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 151.41 (CH), 146.47, 146.37,
Methyl 2-Phenyl-1-naphthoate (5a): Colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 8.00–7.95 (m, 2 H), 7.91 (dd, J = 8.0,
1.6 Hz, 1 H), 7.60–7.38 (m, 8 H), 3.71 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 170.09, 140.92, 138.08, 132.33, 130.00
139.40, 134.87, 134.54 (CH), 133.70 (CH), 130.85 (CH), 129.62 (CH), 129.95, 128.53 (2 CH), 128.48 (2 CH), 128.17 (CH), 127.64
(CH), 128.97 (CH), 128.62, 123.40 (CH), 116.67, 107.71, 21.30
(CH3) ppm. HRMS (EI): calcd. for C17H12N2 244.1000; found
244.0995.
(CH), 127.51 (CH), 127.44 (CH), 126.38 (CH), 125.09 (CH), 52.23
(CH3) ppm. MS (EI): m/z (%) = 262 (85) [M]+, 231 (100). HRMS
(EI): calcd. for C18H14O2 262.0994; found 236.0991.
6-[2-(Trifluoromethyl)phenyl]quinoline-5-carbonitrile (4e): Colorless
crystalline solid; m.p. 135–136 °C. H NMR (400 MHz, CDCl3): δ
Methyl 2-(m-Tolyl)-1-naphthoate (5b): Colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.97–7.93 (m, 2 H), 7.89 (dd, J = 8.4,
1.6 Hz, 1 H), 7.59–7.50 (m, 3 H), 7.35–7.26 (m, 3 H), 7.20 (d, J =
7.6 Hz, 1 H), 3.71 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.16, 140.84, 138.17, 138.13, 132.29, 130.01, 129.93
(CH), 129.87, 129.25 (CH), 128.41 (CH), 128.36 (CH), 128.15
(CH), 127.49 (CH), 127.45 (CH), 126.30 (CH), 125.59 (CH), 125.08
1
= 9.09 (dd, J = 4.2, 1.6 Hz, 1 H), 8.60 (ddd, J = 8.5, 1.6, 0.9 Hz,
1 H), 8.36 (dd, J = 8.8, 0.8 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 7.75–
7.62 (m, 4 H), 7.45 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 152.16 (CH), 146.84, 144.31, 136.65, 133.74 (CH),
131.92 (CH), 131.43 (CH), 130.83 (CH), 129.40 (CH), 128.82 (d, J
= 30.2 Hz, C-CF3), 127.85, 126.60 (q, J = 5.0 Hz, CH-C-CF3), (CH), 52.21 (CH3), 21.52 (CH3) ppm. MS (EI): m/z (%) = 276 (88)
123.71 (d, J = 274.7 Hz, CF3) 123.70 (CH), 115.40, 110.45 ppm.
[M]+, 245 (100). HRMS (EI): calcd. for C19H16O2 276.1150; found
MS (EI): m/z (%) = 298 (100) [M]+. HRMS (EI): calcd. for 276.1149.
C17H9F3N2 298.0718; found 298.0721.
Methyl 2-[3-(Trifluoromethyl)phenyl]-1-naphthoate (5c): Colorless
6-[3-(Trifluoromethyl)phenyl]quinoline-5-carbonitrile (4f): Light yel-
low solid; m.p. 118–120 °C. 1H NMR (400 MHz, CDCl3): δ = 9.08
oil. 1H NMR (400 MHz, CDCl3): δ = 8.00–7.94 (m, 2 H), 7.91 (dd,
J = 7.6, 1.6 Hz, 1 H), 7.75 (s, 1 H), 7.68–7.63 (m, 2 H), 7.61–7.54
(dd, J = 4.2, 1.6 Hz, 1 H), 8.65 (d, J = 8.4 Hz, 1 H), 8.42 (d, J = (m, 3 H), 7.50 (d, J = 8.4 Hz, 1 H), 3.72 (s, 3 H) ppm. 13C NMR
8.8 Hz, 1 H), 7.93–7.89 (m, 2 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.79
(d, J = 7.8 Hz, 1 H), 7.72–7.66 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 152.12 (CH), 146.82, 144.63, 138.60, 135.11 (CH),
(125 MHz, CDCl3): δ = 169.64, 141.66, 136.39, 132.58, 131.92
(CH), 131.04, 130.78, 130.33 (CH), 129.94, 128.97 (CH), 128.21
(CH), 127.77 (CH), 126.92 (CH), 126.80 (CH), 125.37 (q, J =
133.88 (CH), 132.50 (CH), 131.51 (d, J = 32.7 Hz, C-CF3), 130.45 3.8 Hz, CH), 125.20 (CH), 124.39 (q, J = 3.8 Hz, CH), 122.98,
(CH), 129.55 (CH), 128.60, 126.03 (m, 2 CH-C-CF3), 123.82 (d, J 52.26 (CH3) ppm. MS (EI): m/z (%) = 330 (90) [M]+, 299 (100).
= 273.4 Hz, CF3), 123.81 (CH), 116.09, 108.62 ppm. MS (EI): m/z
(%) = 298 (100) [M]+. HRMS (EI): calcd. for C17H9F3N2 298.0718;
found 298.0716.
HRMS (EI): calcd. for C19H13F3O2 330.0868; found 330.0871.
Ethyl 6-Phenylisoquinoline-5-carboxylate (5d): Light yellow solid;
m.p. 98–100 °C. 1H NMR (400 MHz, CDCl3): δ = 9.31 (s, 1 H),
8.62 (d, J = 6.0 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.85 (d, J =
6-(Furan-2-yl)quinoline-5-carbonitrile (4g): Yellow solid; m.p. 159–
160 °C. 1H NMR (400 MHz, CDCl3): δ = 8.95 (dd, J = 4.2, 1.5 Hz, 6.0 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.47–7.42 (m, 5 H), 4.17
1 H), 8.57 (dd, J = 8.5, 0.7 Hz, 1 H), 8.28 (d, J = 9.1 Hz, 1 H),
8.20 (d, J = 9.1 Hz, 1 H), 7.65 (dd, J = 2.0, 0.8 Hz, 1 H), 7.58 (dd,
J = 8.5, 4.2 Hz, 1 H), 7.50 (d, J = 3.6 Hz, 1 H), 6.63 (dd, J = 3.6,
1.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 151.33 (CH),
149.60, 146.45, 144.41 (CH), 134.82 (CH), 133.69, 133.55 (CH),
(q, J = 7.2 Hz, 2 H), 0.97 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 168.38, 152.82 (CH), 144.73 (CH), 143.03,
140.45, 133.16, 129.79 (CH), 129.22 (CH), 129.05, 128.72 (CH),
128.64 (CH), 128.34 (CH), 127.44, 117.98 (CH), 61.78 (CH2), 13.82
(CH3) ppm. MS (EI): m/z (%) = 277 (65) [M]+, 232 (100). HRMS
128.89, 126.67 (CH), 123.61 (CH), 116.86, 112.81 (CH), 112.58 (EI): calcd. for C18H15NO2 277.1103; found 277.1111.
(CH), 102.62 ppm. MS (EI): m/z (%) = 220 (100) [M]+. HRMS
Ethyl 6-(m-Tolyl)isoquinoline-5-carboxylate (5e): Light yellow solid;
(EI): calcd. for C14H8N2O 220.0637; found 220.0637.
m.p. 74–76 °C. 1H NMR (400 MHz, CDCl3): δ = 9.32 (s, 1 H), 8.63
6-(Thiophen-2-yl)quinoline-5-carbonitrile (4h): Yellow powder; m.p. (s, 1 H), 8.09 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 5.0 Hz, 1 H), 7.66
154–155 °C. 1H NMR (400 MHz, CDCl3): δ = 8.99 (dd, J = 4.2,
1.6 Hz, 1 H), 8.60 (ddd, J = 8.5, 1.5, 0.8 Hz, 1 H), 8.30 (d, J =
(d, J = 8.5 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.30–7.22 (m, 3 H),
4.20 (q, J = 7.1 Hz, 2 H), 2.42 (s, 3 H), 1.01 (t, J = 7.1 Hz, 3
Eur. J. Org. Chem. 2012, 6622–6629
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6627

Y. Wang, C. Tan, X. Zhang, Q. He, Y. Xie, C. Yang
FULL PAPER
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 163.09, 147.41 (CH),
139.28 (CH), 137.77, 134.98, 133.03, 127.78, 124.36 (CH), 123.97
(CH), 123.92 (CH), 123.70 (CH), 123.61, 123.28 (CH), 120.39
(CH), 112.65 (CH), 56.39 (CH2), 16.27 (CH3), 8.49 (CH3) ppm. MS
(EI): m/z (%) = 291 (65) [M]+, 246 (100). HRMS (EI): calcd. for
C19H17NO2 291.1259; found 291.1260.
E. J. Lavoie, A. Parhi, D. S. Pilch, PCT Int. Patent Appl. WO
2011163610 A2, 2011.
[4]
[5]
a) M. Wetzel, S. Marchais-Oberwinkler, E. Perspicace, G.
Möller, J. Adamski, R. W. Hartmann, J. Med. Chem. 2011, 54,
7547; b) R. D. Dally, J. A. Dodge, S. A. Frank, R. J. Hinklin,
T. A. Shepherd, O. B. Wallace, R. Dally, J. Dodge, S. Frank, R.
Hinklin, T. Shepherd, O. Wallace, R. J. Hinkein, T. A. Sheperd,
R. D. Daelri, J. A. Datji, S. A. Peuraengkeu, R. J. Hinkeulrin,
T. A. Syepeodeu, O. B. Wolreseu, PCT Int. Patent Appl. WO
05073204 A1, 2005; c) Z. Wang, Y. Li, C. Ai, Y. Wang, Int. J.
Mol. Sci. 2010, 11, 3434.
a) R. L. Shepard, J. J. Starling, M. A. Winter, S. Chandrasek-
har, A. H. Dantzig, U. S. Patent 6124311 A, 2000; b) X. Wang,
K. Nakagawa-Goto, K. F. Bastow, M.-J. Don, Y.-L. Lin, T.-S.
Wu, K.-H. Lee, J. Med. Chem. 2006, 49, 5631; c) Z. Xia, R. G.
Correa, J. K. Das, L. Farhana, D. J. Castro, J. Yu, R. G. Osh-
ima, J. A. Fontana, J. C. Reed, M. I. Dawson, J. Med. Chem.
2012, 55, 233.
a) O. G. Schramm, T. Oeser, M. Kaiser, R. Brun, T. J. J. Müller,
Synlett 2008, 359; b) J. Wiesner, R. Ortmann, H. Jomaa, M.
Schlitzer, Angew. Chem. 2003, 115, 5432; Angew. Chem. Int. Ed.
2003, 42, 5274.
a) A. Kamal, M. K. Reddy, M. J. Ramaiah, Y. V. V. Srikanth,
Rajender, V. S. Reddy, G. B. Kumar, S. N. C. V. L. Pushpavalli,
I. Bag, A. Juvekar, S. Sen, S. M. Zingde, M. Pal-Bhadra, Chem-
MedChem 2011, 6, 1665; b) M. K. Kharel, L. Zhu, T. Liu, J.
Rohr, J. Am. Chem. Soc. 2007, 129, 3780; c) H. Nakano, Y.
Matsuda, K. Ito, S. Ohkubo, M. Morimoto, F. Tomita, J. Anti-
biot. 1981, 34, 266–270.
Ethyl 6-[3-(Trifluoromethyl)phenyl]isoquinoline-5-carboxylate (5f):
White solid; m.p. 114–116 °C. 1H NMR (500 MHz, CDCl3): δ =
9.38 (s, 1 H), 8.68 (d, J = 5.4 Hz, 1 H), 8.17 (d, J = 8.4 Hz, 1 H),
7.90 (d, J = 5.9 Hz, 1 H), 7.77 (s, 1 H), 7.73 (d, J = 7.7 Hz, 1 H),
7.70–7.65 (m, 2 H), 7.63 (t, J = 7.7 Hz, 1 H), 4.22 (q, J = 7.2 Hz,
2 H), 1.04 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 167.71, 152.72 (CH), 144.79 (CH), 141.20, 141.09, 132.98,
131.87 (CH), 130.01 (CH), 129.31, 129.11 (CH), 128.59 (CH),
127.50, 125.34 (q, J = 3.8 Hz, CH-C-CF3), 124.92 (q, J = 3.8 Hz,
CH-C-CF3), 122.83, 117.90 (CH), 61.78 (CH2), 13.60 (CH3) ppm.
MS (EI): m/z = 345 (60) [M]+, 300 (100). HRMS (EI): calcd. for
C19H14F3NO2 345.0977; found 345.0975.
Ethyl 7-Phenylquinoline-8-carboxylate (5g): Light yellow oil. 1H
NMR (400 MHz, CDCl3): δ = 9.00 (dd, J = 4.2, 1.7 Hz, 1 H), 8.19
(dd, J = 8.3, 1.7 Hz, 1 H), 7.91 (d, J = 8.5 Hz, 1 H), 7.59 (d, J =
8.4 Hz, 1 H), 7.58–7.54 (m, 2 H), 7.48–7.40 (m, 4 H), 4.31 (q, J =
7.1 Hz, 2 H), 1.05 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.88, 151.39 (CH), 145.27, 140.33, 139.62, 135.72
(CH), 132.52, 128.85 (CH), 128.66 (CH), 128.38 (CH), 128.14
(CH), 127.92 (CH), 126.90, 121.48 (CH), 61.41 (CH2), 13.78
(CH3) ppm.
[6]
[7]
[8]
[9]
M. Hagihara, H. Nishida, Y. Tsuzaki, K. Yoshimura, K.-i. Ko-
mori, T. Matsugi, M. Hatano, H. Hara, PCT Int. Patent Appl.
WO 05035503 A1, 2005.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for all new products.
[10]
a) C. S. Cho, N. Y. Lee, H.-J. Choi, T.-J. Kim, S. C. Shim, J.
Heterocycl. Chem. 2003, 40, 929; b) J. A. Sebree, N. M.
Kidwell, T. M. Selby, B. K. Amberger, R. J. McMahon, T. S.
Zwier, J. Am. Chem. Soc. 2011, 134, 1153; c) R.-G. Xing, Y.-
N. Li, Q. Liu, Y.-F. Han, X. Wei, J. Li, B. Zhou, Synthesis
2011, 2066; d) B. H. Kim, J. G. Lee, T. Yim, H.-J. Kim, H. Y.
Lee, Y. G. Kim, Tetrahedron Lett. 2006, 47, 7727; e) T. K.
Macklin, V. Snieckus, Org. Lett. 2005, 7, 2519; f) A. S. Dudnik,
T. Schwier, V. Gevorgyan, Tetrahedron 2009, 65, 1859; g) A. S.
Dudnik, T. Schwier, V. Gevorgyan, Org. Lett. 2008, 10, 1465;
h) H.-C. Shen, S. Pal, J.-J. Lian, R.-S. Liu, J. Am. Chem. Soc.
2003, 125, 15762; i) C. Wolf, R. Lerebours, J. Org. Chem. 2003,
68, 7551; j) T. Tagata, M. Nishida, J. Org. Chem. 2003, 68,
9412; k) C. M. So, H. W. Lee, C. P. Lau, F. Y. Kwong, Org.
Lett. 2008, 10, 317; l) C. M. So, C. P. Lau, A. S. C. Chan, F. Y.
Kwong, J. Org. Chem. 2008, 73, 7731; m) A. K. Sahoo, T. Oda,
Y. Nakao, T. Hiyama, Adv. Synth. Catal. 2004, 346, 1715; n)
A. R. Jagdale, J. H. Park, S. W. Youn, J. Org. Chem. 2011, 76,
7204; o) R. Aissaoui, A. Nourry, A. Coquel, T. T. H. Dao, A.
Derdour, J.-J. Helesbeux, O. Duval, A.-S. Castanet, J. Mortier,
J. Org. Chem. 2011, 77, 718.
a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; b) J.
Hassan, M. Sévignon, C. Gozzi, E. Schulz, M. Lemaire, Chem.
Rev. 2002, 102, 1359; c) G. A. Molander, N. Ellis, Acc. Chem.
Res. 2007, 40, 275; d) D.-G. Yu, B.-J. Li, S.-F. Zheng, B.-T.
Guan, B.-Q. Wang, Z.-J. Shi, Angew. Chem. 2010, 122, 4670;
Angew. Chem. Int. Ed. 2010, 49, 4566; e) B.-T. Guan, Y. Wang,
B.-J. Li, D.-G. Yu, Z.-J. Shi, J. Am. Chem. Soc. 2008, 130,
14468; f) J. L. Bolliger, C. M. Frech, Adv. Synth. Catal. 2010,
352, 1075; g) P. Leowanawat, N. Zhang, V. Percec, J. Org.
Chem. 2012, 77, 1018.
Acknowledgments
The authors are grateful to the Ministry of Science and Technology
of China (Chinese National Science & Technology Major Project
“Key New Drug Creation and Manufacturing Program”, grant
number 2012ZX09301001-001), the Chinese Academy of Sciences
(“Interdisciplinary Cooperation Team” Program for Science and
Technology Innovation), the National Natural Science Foundation
of China (NSFC) (grant number 21072205), and SKLDR/SIMM
(SIMM1203ZZ-0103).
[1] a) M. Wetzel, S. Marchais-Oberwinkler, R. W. Hartmann, Bi-
oorg. Med. Chem. 2011, 19, 807; b) J. S. Blakeney, R. C. Reid,
G. T. Le, D. P. Fairlie, Chem. Rev. 2007, 107, 2960; c) R. E.
Mewshaw, R. J. Edsall, C. Yang, E. S. Manas, Z. B. Xu, R. A.
Henderson, J. C. Keith, H. A. Harris, J. Med. Chem. 2005, 48,
3953; d) X. Zhang, M. A. Campo, T. Yao, R. C. Larock, Org.
Lett. 2005, 7, 763; e) Y. Cheng, T. C. Judd, M. D. Bartberger,
J. Brown, K. Chen, R. T. Fremeau, D. Hickman, S. A. Hitch-
cock, B. Jordan, V. Li, P. Lopez, S. W. Louie, Y. Luo, K. Mich-
elsen, T. Nixey, T. S. Powers, C. Rattan, E. A. Sickmier, D. J.
St. Jean, R. C. Wahl, P. H. Wen, S. Wood, J. Med. Chem. 2011,
54, 5836; f) A. Gopalsamy, K. Lim, J. W. Ellingboe, G. Krishn-
amurthy, M. Orlowski, B. Feld, M. van Zeijl, A. Y. M. Howe,
Bioorg. Med. Chem. Lett. 2004, 14, 4221.
[2] C. B. de Koning, A. L. Rousseau, W. A. L. van Otterlo, Tetra-
hedron 2003, 59, 7.
[3] J. S. Albert, C. Ohnmacht, P. R. Bernstein, W. L. Rumsey, D.
Aharony, Y. Alelyunas, D. J. Russell, W. Potts, S. A. Sherwood,
L. Shen, R. F. Dedinas, W. E. Palmer, K. Russell, J. Med.
Chem. 2003, 47, 519.
[11]
[12]
a) N. Asao, T. Nogami, S. Lee, Y. Yamamoto, J. Am. Chem.
Soc. 2003, 125, 10921; b) N. Asao, K. Takahashi, S. Lee, T.
Kasahara, Y. Yamamoto, J. Am. Chem. Soc. 2002, 124, 12650;
c) N. Asao, Menggenbateer, Y. Seya, Y. Yamamoto, M. Chen,
W. Zhang, A. Inoue, Synlett 2012, 23, 66; d) N. Asao, H. Ai-
kawa, Y. Yamamoto, J. Am. Chem. Soc. 2004, 126, 7458; e) Z.
6628
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6622–6629

A Microwave-Assisted Domino Benzannulation Reaction
Huo, H. D. Gridnev, Y. Yamamoto, J. Org. Chem. 2010, 75,
1266.
[19]
[20]
M. Chaumontet, R. Piccardi, N. Audic, J. Hitce, J.-L. Peglion,
E. Clot, O. Baudoin, J. Am. Chem. Soc. 2008, 130, 15157.
E. Oishi, N. Taido, K. Iwamoto, A. Miyashita, T. Higashino,
Chem. Pharm. Bull. 1990, 38, 3268.
[13] T. J. J. Müller, M. Ansorge, D. Aktah, Angew. Chem. 2000, 112,
1323; Angew. Chem. Int. Ed. 2000, 39, 1253.
[14] T. J. J. Müller, R. Braun, M. Ansorge, Org. Lett. 2000, 2, 1967.
[15] R. U. Braun, K. Zeitler, T. J. J. Müller, Org. Lett. 2000, 2, 4181.
[16] R. U. Braun, K. Zeitler, T. J. J. Müller, Org. Lett. 2001, 3, 3297.
[17] N. A. M. Yehia, K. Polborn, T. J. J. Müller, Tetrahedron Lett.
2002, 43, 6907.
[21] M. Lysén, M. Madden, J. L. Kristensen, P. Vedsø, C. Zøllner,
M. Begtrup, Synthesis 2006, 3478.
[22] B. Mariampillai, J. Alliot, M. Li, M. Lautens, J. Am. Chem.
Soc. 2007, 129, 15372.
Received: August 6, 2012
Published Online: October 9, 2012
[18] O. G. Schramm, N. Dediu, T. Oeser, T. J. J. Müller, J. Org.
Chem. 2006, 71, 3494.
Eur. J. Org. Chem. 2012, 6622–6629
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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