An Efficient One-pot Three-component Process for Synthesis of Perfluoroalkylated Quinolizines

Article abstract of DOI:10.1002/cjoc.201500872

A facile multi-component process for the synthesis of perfluoroalkylated quinolizine derivatives was achieved using various arylidenemalononitriles, pyridine, and methyl perfluoroalk-2-ynoates as starting materials. Moderate yields were obtained under mil

Full text of DOI:10.1002/cjoc.201500872

FULL PAPER
DOI: 10.1002/cjoc.201500872
An Efficient One-pot Three-component Process for
Synthesis of Perfluoroalkylated Quinolizines
Dandan Shen,a Yanjie Xu,a Dong He,a Jing Han,a Jie Chen,a Hongmei Deng,b
Min Shao,b Hui Zhang,*,a,b and Weiguo Cao*,a,c,d,e
a Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
b Laboratory for Microstructures, Instrumental Analysis and Research Center of Shanghai University, Shanghai
200444, China
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
d Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
e Key Laboratory of Synthetic Organic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
A facile multi-component process for the synthesis of perfluoroalkylated quinolizine derivatives was achieved
using various arylidenemalononitriles, pyridine, and methyl perfluoroalk-2-ynoates as starting materials. Moderate
yields were obtained under mild condition. The structures of perfluoroalkylated quinolizine derivatives were char-
acterized by means of 1H NMR, 13C NMR, 19F NMR, IR, LRMS and HRMS. Furthermore, the reaction mechanism
was proposed.
Keywords quinolizines, perfluoroalkylated, multi-component, one-pot reaction
Introduction
alk-2-ynoates.
Quinolizine skeleton has received constant attention
as it is widely distributed in natural products, especially
in alkaloid, such as lupinine, berberine, emetine, sparte-
ine, etc.[1] Quinolizine derivatives exhibit excellent bio-
logical activities,[2] including anti-HIV, antitumor, anti-
bacterial, anti-allergic, anti-ulcer, and anti-hypertensive
activities. Multi-component reactions (MCRs) for the
synthesis of quinolizine derivatives have been widely
reported recently,[3] because MCRs have the following
inherent characteristics, i.e., chemo- and regioselectivity,
atom economy, step efficiency, diversity, and opera-
tional simplicity, etc. On the other hand, incorporation
of fluorine atom or fluoroalkyl group into organic com-
pounds has aroused great interest in the field of modern
organic chemistry. However, there were few reports on
the synthesis of fluorine-containing quinolizines.[4]
In the context of our general interest in the construc-
tion of perfluoroalkylated heterocycles via multi-com-
ponent reactions (MCRs) using methyl perfluoro-
alk-2-ynoates as fluorinated building blocks,[5] we de-
scribe here a facile synthesis of perfluoroalkylated qui-
nolizines via a one-pot three-component reaction of
pyridine, arylidenemalononitriles and methyl perfluoro-
Experimental
General
Commercially available reagents were used without
further purification. Arylidenemalononitriles 1[6] and
methyl perfluoroalk-2-ynoates 3[7] were prepared ac-
cording to the known literatures. Solvents were distilled
before use. Melting points were recorded on a WRS-1
instrument and uncorrected. 1H, 19F and 13C NMR spec-
tra were recorded on a Bruker DRX-500 MHz spec-
trometer. All chemical shifts are reported in parts per
million downfield (positive) of the standard: CFCl3 for
19F, TMS for 1H and 13C NMR spectra. IR spectra were
obtained on an AVATAR370 FT-IR spectrometer.
LRMS (lower resolution mass spectra) were obtained on
Agilent 5973N MSD or apex-III and HRMS (high reso-
lution mass spectra) were obtained on Waters Micro-
mass GCT Premier, Thermo Fisher Scientific LTQFT
Ultra or Bruker Daltonics, Inc. APEXIII 7.0 TESLA
FTMS. X-ray analysis was performed on a Bruker
Smart Apex2 CCD spectrometer. All yields reported in
this publication refer to the total yield of the two di-
*
E-mail: wgcao@shu.edu.cn; yehao7171@shu.edu.cn; Tel.: 0086-021-66134856; Fax: 0086-021-66134856
Received December 11, 2015; accepted January 11, 2016; published online March 8, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500872 or from the author.
524
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Chin. J. Chem. 2016, 34, 524—532

An Efficient One-pot Three-component Process for Synthesis of Perfluoroalkylated Quinolizines
7.82－7.85 (m, 3H), 7.99－8.00 (m, 2H).
2-(3-Cyanobenzylidene)malononitrile
Red solid, yield 56%. H NMR (500 MHz, CDCl3) δ:
7.70－7.73 (m, 1H), 7.79 (s, 1H), 7.89－7.91 (m, 1H),
8.07－8.08 (m, 1H), 8.20－8.21 (m, 1H).
astereomers and their ratios were determined on the ba-
sis of 19F NMR spectroscopy of the mixtures.
(1n)[6a]
1
General procedure for preparation of compound 1
Malononitrile (10.0 mmol) was added to a stirred
solution of benzaldehyde (10.0 mmol) and piperidine
(1.0 mmol) in ethanol (10 mL). The reaction mixture
was stirred at room temperature for 5 h. A precipitate
was formed and collected by suction filtration, washed
with n-hexane/ethanol (V/V＝10∶1), and then dried
under high vacuum.
2-(4-(Trifluoromethyl)benzylidene)malononitrile
1
(1o)[6f] White solid, yield 89%. H NMR (500 MHz,
CDCl3) δ: 7.76－7.77 (m, 2H), 7.07－7.09 (m, 2H),
8.28 (s, 1H).
2-(4-Fluorobenzylidene)malononitrile
(1p)[6g]
White solid, yield 85%. 1H NMR (500 MHz, CDCl3) δ:
7.22－7.26 (m, 2H), 7.74 (s, 1H), 7.95－7.98 (m, 2H).
2-Benzylidenemalononitrile (1a)[6a] White solid,
1
Methyl
4-(2,2-dicyanovinyl)benzoate
(1q)[6h]
yield 89%. H NMR (500 MHz, CDCl3) δ: 7.53－7.56
1
(m, 2H), 7.62－7.65 (m, 1H), 7.79 (s, 1H), 7.90－7.92
Pale yellow solid, yield 70%. H NMR (500 MHz,
CDCl3) δ: 3.89 (s, 3H), 7.45 (d, J＝8.0 Hz, 2H), 7.67 (d,
J＝8.0 Hz, 2H), 7.79 (s, 1H).
(m, 2H).
2-(4-Methylbenzylidene)malononitrile
(1b)[6b]
White solid, yield 80%. 1H NMR (500 MHz, CDCl3) δ:
2.46 (s, 3H), 7.34 (d, J＝7.5 Hz, 2H), 7.72 (s, 1H), 7.81
(d, J＝7.5 Hz, 2H).
2-(4-Methoxybenzylidene)malononitrile
(1r)[6a]
1
Pale yellow solid, yield 64%. H NMR (500 MHz,
CDCl3) δ: 3.91 (s, 3H), 7.01 (d, J＝9.0 Hz, 2H), 7.65 (s,
1H), 7.91 (d, J＝9.0 Hz, 2H).
2-(3-Methylbenzylidene)malononitrile
(1c)[6c]
White solid, yield 76%. 1H NMR (500 MHz, CDCl3) δ:
2.43 (s, 3H), 7.43－7.44 (m, 2H), 7.69－7.74 (m, 3H).
General procedure for preparation of compounds 4
and 5
2-(2-Methylbenzylidene)malononitrile
(1d)[6c]
White solid, yield 68%. 1H NMR (500 MHz, CDCl3) δ:
2.45 (s, 3H), 7.32－7.37 (m, 2H), 7.48－7.51 (m, 1H),
8.08－8.10 (m, 2H).
To a solution of arylidenemalononitriles 1 (1.0
mmol) and pyridine 2 (1.5 mmol) in acetonitrile (3 mL),
methyl perfluoroalk-2-ynoates 3 (2.0 mmol) was added.
The mixture was stirred at 0 ℃ for 0.5 h. Then the
solvent was removed under vacuum, the residue was
purified by column chromatography on silica gel by
eluting with petroleum ether/ethyl acetate (20∶1 to
10∶1) to afford the desired products 4a－4u, 5a－5u.
cis-Methyl 1,1-dicyano-2-phenyl-4-(trifluoro-
methyl)-1,9a-dihydro-2H-quinolizine-3-carboxylate
(4a) and trans-methyl 1,1-dicyano-2-phenyl-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (5a) Light yellow solid, yield 81%. m.p.
145.8－146.7 ℃.
2-(4-Chlorobenzylidene)malononitrile
(1e)[6b]
White solid, yield 75%. 1H NMR (500 MHz, CDCl3) δ:
7.51－7.53 (m, 2H), 7.73 (s, 1H), 7.85－7.87 (m, 2H).
2-(3-Chlorobenzylidene)malononitrile
(1f)[6b]
White solid, yield 70%. 1H NMR (500 MHz, CDCl3) δ:
7.48－7.52 (m, 1H), 7.59－7.61 (m, 1H), 7.73 (s, 1H),
7.82－7.83 (m, 2H).
2-(2-Chlorobenzylidene)malononitrile
(1g)[6b]
White solid, yield 58%. 1H NMR (500 MHz, CDCl3) δ:
7.44－7.47 (m, 1H), 7.54－7.56 (m, 2H), 8.18－8.19
(m, 1H), 8.27 (s, 1H).
2-(2,3-Dichlorobenzylidene)malononitrile (1h)[6d]
White solid, yield 55%. 1H NMR (500 MHz, CDCl3) δ:
7.39－7.43 (m, 1H), 7.70－7.72 (m, 1H), 8.00－8.02
(m, 1H), 8.26 (s, 1H).
4a: 1H NMR (500 MHz, CDCl3) δ: 3.50 (s, 3H), 4.55
(s, 1H), 5.06 (d, J＝4.5 Hz, 1H), 5.15－5.18 (m, 1H),
5.71－5.74 (m, 1H), 6.30－6.33 (m, 2H), 7.41 (s, 5H);
19F NMR (470 MHz, CDCl3) δ: 59.6 (s, CF3).
2-(2,4-Dichlorobenzylidene)malononitrile (1i)[6b]
White solid, yield 54%. 1H NMR (500 MHz, CDCl3) δ:
7.43－7.45 (m, 1H), 7.57－7.58 (m, 1H), 8.14－8.16
(m, 1H), 8.19 (s, 1H).
5a: 1H NMR (500 MHz, CDCl3) δ: 3.57 (s, 3H), 4.38
(s, 1H), 4.65－4.66 (m, 1H), 5.29－5.31 (m, 1H), 5.65
－5.67 (m, 1H), 6.30－6.33 (m, 1H), 6.61－6.63 (m,
1H), 7.29－7.30 (m, 2H), 7.41 (s, 3H); 19F NMR (470
MHz, CDCl3) δ: 59.3 (s, CF3).
2-(2,4-Dimethylbenzylidene)malononitrile (1j)[6e]
1
Pale yellow solid, yield 60%. H NMR (500 MHz,
13C NMR (125 MHz, CDCl3) δ: 41.7, 44.2, 48.4,
51.8, 52.8, 53.0, 56.6, 62.6, 101.5, 103.0, 111.4, 111.8,
CDCl3) δ: 2.30 (s, 3H), 2.41 (s, 3H), 7.03－7.07 (m,
2H), 7.47－7.48 (s, 1H), 8.06 (s, 1H).
1
112.0, 119.9 (q, JC-F＝276.5 Hz, CF3), 120.1, 127.0,
2-(4-Nitrobenzylidene)malononitrile
(1k)[6a]
127.4, 129.1, 129.3, 130.0, 130.4, 131.1, 133.1 (q,
2JC-F＝34.5 Hz, CF3), 164.9; IR (KBr) ν: 2957, 2372,
2250, 1726, 1637, 1587, 1265, 1178, 985, 705 cm1; MS
(EI) m/z: 385 [M]＋. HRMS (EI) calcd for C20H14F3N3O2
[M]＋: 385.1038; found 385.1036.
cis-Methyl 1,1-dicyano-2-(p-tolyl)-4-(trifluoro-
methyl)-1,9a-dihydro-2H-quinolizine-3-carboxylate
(4b) and trans-methyl 1,1-dicyano-2-(p-tolyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
Brown solid, yield 78%. 1H NMR (500 MHz, CDCl3) δ:
7.88 (s, 1H), 8.07－8.08 (m, 2H), 8.38－8.40 (m, 2H).
2-(3-Nitrobenzylidene)malononitrile
(1l)[6a]
Brown solid, yield 77%. 1H NMR (500 MHz, CDCl3) δ:
7.18－7.81 (m, 1H), 7.90 (s, 1H), 8.32－8.33 (m, 1H),
8.46－8.48 (m, 1H), 8.66－8.67 (m, 1H).
2-(4-Cyanobenzylidene)malononitrile
(1m)[6a]
1
Red solid, yield 57%. H NMR (500 MHz, CDCl3) δ:
Chin. J. Chem. 2016, 34, 524—532
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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525

Shen et al.
FULL PAPER
carboxylate (5b) Light yellow solid, yield 82%. m.p.
156.5－157.3 ℃.
－5.76 (m, 1H), 6.32－6.35 (m, 1H), 6.64－6.65 (m,
1H), 7.09－7.10 (m, 1H), 7.22－7.25 (m, 1H) 7.27－
7.30 (m, 2H); 19F NMR (470 MHz, CDCl3) δ: 59.4 (s,
CF3).
4b: 1H NMR (500 MHz, CDCl3) δ: 2.36 (s, 3H), 3.52
(s, 3H), 4.51 (s, 1H), 5.05 (d, J＝4.5 Hz, 1H), 5.14－
5.17 (m, 1H), 5.70－5.73 (m, 1H), 6.29－6.32 (m, 2H),
7.16－7.19 (m, 2H), 7.28－7.30 (m, 2H); 19F NMR
(470 MHz, CDCl3) δ: 59.6 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 19.6, 41.9, 42.5,
44.2, 46.2, 52.7, 56.9, 60.4, 63.2, 101.5, 102.9, 111.5,
1
111.8, 112.2, 119.0 (q, JC-F＝276.0 Hz, CF3), 121.4,
5b: 1H NMR (500 MHz, CDCl3) δ: 2.36 (s, 3H), 3.58
(s, 3H), 4.34 (s, 1H), 4.63－4.64 (m, 1H), 5.27－5.30
(m, 1H), 5.64－5.67 (m, 1H), 6.29－6.32 (m, 1H),
6.60－6.62 (m, 1H), 7.16－7.19 (m, 2H), 7.21－7.23
(m, 2H); 19F NMR (470 MHz, CDCl3) δ: 59.3 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 21.3, 41.9, 44.4,
48.1, 51.5, 52.8, 53.0, 56.5, 62.6, 101.4, 102.9, 111.5,
126.4, 126.6, 127.0, 127.5, 128.4, 129.3, 129.4, 129.8,
2
131.4, 132.2 (q, JC-F＝34.3 Hz, CF3), 137.8, 164.9; IR
(KBr) ν: 2955, 2372, 2249, 1720, 1645, 1586, 1275,
1189, 1141, 928, 731 cm1; MS (EI) m/z: 399 [M]＋.
HRMS (EI) calcd for C21H16F3N3O2 [M]＋: 399.1195;
found 399.1199.
cis-Methyl 2-(4-chlorophenyl)-1,1-dicyano-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4e) and trans-methyl 2-(4-chlorophe-
nyl)-1,1-dicyano-4-(trifluoromethyl)-1,9a-dihydro-
2H-quinolizine-3-carboxylate (5e) White solid, yield
85%. m.p. 145.2－146.1 ℃.
1
111.8, 112.1, 120.0 (q, JC-F＝276.4 Hz, CF3), 120.4,
126.9, 127.3, 127.9, 128.3, 128.9, 129.3, 129.8, 132.9 (q,
2JC-F＝34.4 Hz, CF3), 140.1, 164.9; IR (KBr) ν: 2954,
2256, 2221, 1738, 1647, 1583, 1256, 1190, 1143, 982,
732 cm1; MS (EI) m/z: 399 [M]＋. HRMS (EI) calcd for
C21H16F3N3O2 [M]＋: 399.1195; found 399.1191.
cis-Methyl 1,1-dicyano-2-(m-tolyl)-4-(trifluoro-
methyl)-1,9a-dihydro-2H-quinolizine-3-carboxylate
(4c) and trans-methyl 1,1-dicyano-2-(m-tolyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (5c) Light yellow solid, yield 84%. m.p.
142.3－143.2 ℃.
4e: 1H NMR (500 MHz, CDCl3) δ: 3.54 (s, 3H), 4.54
(s, 1H), 5.05 (d, J＝4.5 Hz, 1H), 5.17－5.19 (m, 1H),
5.71－5.73 (m, 1H), 6.29－6.34 (m, 2H), 7.35－7.40
(m, 4H); 19F NMR (470 MHz, CDCl3) δ: 59.6 (s, CF3).
5e: 1H NMR (500 MHz, CDCl3) δ: 3.60 (s, 3H), 4.35
(s, 1H), 4.58－4.59 (m, 1H), 5.30－5.32 (m, 1H), 5.65
－5.67 (m, 1H), 6.29－6.34 (m, 1H), 6.61－6.62 (m,
1H), 7.23－7.24 (m, 1H), 7.35－7.40 (m, 3H); 19F NMR
(470 MHz, CDCl3) δ: 59.3 (s, CF3).
4c: 1H NMR (500 MHz, CDCl3) δ: 2.37 (s, 3H), 3.51
(s, 3H), 4.50 (s, 1H), 5.05 (d, J＝4.5 Hz, 1H), 5.15－
5.17 (m, 1H), 5.71－5.74 (m, 1H), 6.30－6.33 (m, 2H),
7.19－7.21 (m, 3H), 7.23－7.27 (m, 1H); 19F NMR
(470 MHz, CDCl3) δ: 59.6 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 41.6, 44.0, 47.6,
51.1, 53.0, 56.6, 58.4, 62.5, 101.6, 103.1, 111.3, 111.8,
1
111.9, 119.4, 119.9 (q, JC-F＝276.6 Hz, CF3), 127.1,
5c: 1H NMR (500 MHz, CDCl3) δ: 2.38 (s, 3H), 3.58
(s, 3H), 4.33 (s, 1H), 4.65－4.66 (m, 1H), 5.29－5.31
(m, 1H), 5.66－5.68 (m, 1H), 6.30－6.33 (m, 1H),
6.61－6.63 (m, 1H), 7.05－7.08 (m, 2H), 7.19－7.21
(m, 1H), 7.23－7.27 (m, 1H); 19F NMR (470 MHz,
CDCl3) δ: 59.3 (s, CF3).
127.4, 129.1, 129.4, 129.7, 130.4, 133.4 (q, JC-F＝34.4
2
Hz, CF3), 136.2, 164.7; IR (KBr) ν: 2959, 2371, 2246,
1744, 1647, 1584, 1218, 1186, 1145, 985, 732 cm1; MS
(EI) m/z: 419 [M]＋. HRMS (EI) calcd for C20H13ClF3-
N3O2 [M]＋: 419.0648; found 419.0651.
cis-Methyl 2-(3-chlorophenyl)-1,1-dicyano-4-
(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4f) and trans-methyl 2-(3-chlorophenyl)-
1,1-dicyano-4-(trifluoromethyl)-1,9a-dihydro-2H-
quinolizine-3-carboxylate (5f) White solid, yield
78%. m.p. 143.6－144.4 ℃.
13C NMR (125 MHz, CDCl3) δ: 21.4, 41.8, 44.2,
48.3, 51.7, 52.8, 53.0, 56.6, 62.6, 101.4, 102.9, 111.5,
1
111.8, 112.1, 120.0 (q, JC-F＝276.6 Hz, CF3), 120.3,
126.9, 127.3, 128.9, 129.3, 129.8, 130.8, 131.0, 132.9 (q,
2JC-F＝34.4 Hz, CF3), 139.0, 165.0, 165.6; IR (KBr) ν:
3132, 1725, 1594, 1384, 1231, 1171, 1112, 696 cm1;
MS (EI) m/z: 399 [M] ＋ . HRMS (EI) calcd for
C21H16F3N3O2 [M]＋: 399.1195; found 399.1187.
cis-Methyl 1,1-dicyano-2-(o-tolyl)-4-(trifluoro-
methyl)-1,9a-dihydro-2H-quinolizine-3-carboxylate
(4d) and trans-methyl 1,1-dicyano-2-(o-tolyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (5d) Light yellow solid, yield 80%. m.p.
143.5－144.6 ℃.
4f: 1H NMR (500 MHz, CDCl3) δ: 3.55 (s, 3H), 4.53
(s, 1H), 5.05 (d, J＝4.5 Hz, 1H), 5.17－5.20 (m, 1H),
5.72－5.74 (m, 1H), 6.30－6.34 (m, 2H), 7.31－7.35
(m, 4H); 19F NMR (470 MHz, CDCl3) δ: 59.6 (s, CF3).
5f: 1H NMR (500 MHz, CDCl3) δ: 3.60 (s, 3H), 4.34
(s, 1H), 4.61－4.62 (m, 1H), 5.30－5.32 (m, 1H),
5.67－5.69 (m, 1H), 6.30－6.34 (m, 1H), 6.61－6.63
(m, 1H), 7.20－7.21 (m, 1H), 7.27－7.28 (m, 1H),
7.31－7.35 (m, 2H); 19F NMR (470 MHz, CDCl3) δ:
59.3 (s, CF3).
4d: 1H NMR (500 MHz, CDCl3) δ: 2.49 (s, 3H), 3.42
(s, 3H), 5.00 (s, 1H), 5.12 (d, J＝4.0 Hz, 1H), 5.17－
5.20 (m, 1H), 5.73－5.76 (m, 1H), 6.32－6.35 (m, 2H),
7.22－7.25 (m, 2H), 7.27－7.30 (m, 1H), 7.43－7.44
(m, 1H); 19F NMR (470 MHz, CDCl3) δ: 59.6 (s, CF3).
5d: 1H NMR (500 MHz, CDCl3) δ: 2.53 (s, 3H), 3.53
(s, 3H), 4.68－4.71 (m, 2H), 5.29－5.30 (m, 1H), 5.73
13C NMR (125 MHz, CDCl3) δ: 41.6, 43.8, 47.7,
51.2, 53.0, 56.8, 62.6, 101.7, 103.1, 111.2, 111.7, 111.8
1
119.3, 119.8 (q, JC-F＝276.5 Hz, CF3), 127.1, 127.5,
2
129.1, 130.4, 133.1, 133.5 (q, JC-F＝34.5 Hz, CF3),
135.0, 164.7; IR (KBr) ν: 3132, 1725, 1594, 1384, 1231,
1171, 1112, 696 cm1; MS (EI) m/z: 419 [M]＋. HRMS
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Chin. J. Chem. 2016, 34, 524—532

An Efficient One-pot Three-component Process for Synthesis of Perfluoroalkylated Quinolizines
(EI) calcd for C20H13ClF3N3O2 [M]＋: 419.0648; found
419.0644.
－7.47 (m, 2H); 19F NMR (470 MHz, CDCl3) δ: 59.6
(s, CF3).
5i: 1H NMR (500 MHz, CDCl3) δ: 3.60 (s, 3H), 4.55
cis-Methyl 2-(2-chlorophenyl)-1,1-dicyano-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4g) and trans-methyl 2-(2-chlorophenyl)-
1,1-dicyano-4-(trifluoromethyl)-1,9a-dihydro-2H-
quinolizine-3-carboxylate (5g) White solid, yield
57%. m.p. 142.9－143.6 ℃.
(s, 1H), 4.99－5.00 (m, 1H), 5.31－5.32 (m, 1H), 5.72
－5.78 (m, 1H), 6.30－6.36 (m, 1H), 6.62－6.64 (m,
1H), 7.19－7.20 (s, 1H), 7.31－7.33 (m, 1H), 7.45－
7.47 (m, 1H); 19F NMR (470 MHz, CDCl3) δ: 59.5 (s,
CF3).
13C NMR (125 MHz, CDCl3) δ: 31.6, 41.6, 44.1, 45.9,
53.0, 57.3, 60.4, 63.0, 101.9, 102.9, 111.0, 111.6, 119.5,
4g: 1H NMR (500 MHz, CDCl3) δ: 3.46 (s, 3H), 5.13
(s, 1H), 5.19－5.21 (m, 1H), 5.44 (s, 1H), 5.77－5.78
(m, 1H), 6.33－6.36 (m, 2H), 7.32－7.38 (m, 2H),
7.47－7.52 (m, 2H); 19F NMR (470 MHz, CDCl3) δ:
59.5 (s, CF3).
1
119.8 (q, JC-F＝276.5 Hz, CF3), 127.5, 127.7, 127.8,
129.1, 130.3, 130.5, 133.6 (q, 2JC-F＝34.9 Hz, CF3), 136.4,
136.7, 164.3; IR (KBr) ν: 2938, 2342, 2257, 1728, 1632,
1587, 1266, 1186, 1149, 984, 763 cm1; MS (ESI) m/z:
454 [(M＋H)]＋. HRMS (ESI) calcd for C20H13Cl2F3-
N3O2 [(M＋H)]＋: 454.0331; found 454.0325.
5g: 1H NMR (500 MHz, CDCl3) δ: 3.57 (s, 3H), 4.60
(s, 1H), 5.08－5.09 (m, 1H), 5.30－5.31 (m, 1H), 5.72
－5.73 (m, 1H), 6.33－6.36 (m, 1H), 6.64－6.65 (m,
1H), 7.32－7.38 (m, 3H), 7.47－7.52 (m, 1H); 19F NMR
(470 MHz, CDCl3) δ: 59.4 (s, CF3).
cis-Methyl 1,1-dicyano-2-(2,4-dimethylphenyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4j) and trans-methyl 1,1-dicyano-
2-(2,4-dimethylphenyl)-4-(trifluoromethyl)-1,9a-
13C NMR (125 MHz, CDCl3) δ: 41.8, 44.5, 46.2,
52.8, 57.2, 63.1, 101.8, 102.8, 111.1, 111.6, 119.9 (q,
1JC-F＝276.2 Hz, CF3), 120.2, 127.2, 127.4, 129.1, 129.2,
dihydro-2H-quinolizine-3-carboxylate (5j)
yellow solid, yield 64%. m.p. 166.1－167.2 ℃.
Light
2
129.8, 130.4, 131.2, 133.3 (q, JC-F＝34.2 Hz, CF3),
4j: 1H NMR (500 MHz, CDCl3) δ: 2.31 (s, 3H), 2.44
(s, 3H), 3.44 (s, 3H), 4.95 (s, 1H), 5.10－5.11 (d, J＝4.4
Hz, 1H), 5.16－5.18 (m, 1H), 5.70－5.74 (m, 1H),
6.31－6.34 (m, 2H), 7.03－7.04 (m, 2H), 7.30－7.32
(m, 1H); 19F NMR (470 MHz, CDCl3) δ: 59.6 (s, CF3).
5j: 1H NMR (500 MHz, CDCl3) δ: 2.31 (s, 3H), 2.48
(s, 3H), 3.54 (s, 3H), 4.66 (s, 2H), 5.28－5.30 (m, 1H),
5.70－5.74 (m, 1H), 6.31－6.34 (m, 1H), 6.63－6.64
(m, 1H), 6.95－6.97 (m, 1H), 7.09－7.10 (m, 1H); 19F
NMR (470 MHz, CDCl3) δ: 59.4 (s, CF3).
135.6, 164.4; IR (KBr) ν: 2953, 2369, 2250, 1725, 1640,
1587, 1274, 1190, 1142, 983, 773 cm1; MS (ESI) m/z:
420 [(M＋H)]＋. HRMS (ESI) calcd for C20H14ClF3N3O2
[(M＋H)]＋: 420.0721; found 420.0712.
cis-Methyl 1,1-dicyano-2-(2,3-dichlorophenyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4h) and trans-methyl 1,1-dicyano-
2-(2,3-dichlorophenyl)-4-(trifluoromethyl)-1,9a-dihydro-
2H-quinolizine-3-carboxylate (5h) White solid, yield
50%. m.p. 152.3－152.9 ℃.
13C NMR (125 MHz, CDCl3) δ: 19.5, 20.2, 21.0,
21.1, 42.0, 42.7, 44.0, 46.1, 52.7, 52.9, 56.8, 60.4, 63.2,
101.4, 102.8, 111.6, 111.9, 112.3, 112.0 (q, 1JC-F＝276.4
Hz, CF3), 121.7, 126.1, 127.1, 127.4, 128.2, 132.3 (q,
2JC-F＝35.0 Hz, CF3), 137.6, 139.7, 164.9; IR (KBr) ν:
3132, 1725, 1594, 1384, 1231, 1171, 1112, 696 cm1;
MS (ESI) m/z: 414 [(M＋H)]＋. HRMS (ESI) calcd for
C22H18F3N3O2 [(M＋H)]＋: 414.1347; found 414.1418.
cis-Methyl 1,1-dicyano-2-(4-nitrophenyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4k) and trans-methyl 1,1-dicyano-
2-(4-nitrophenyl)-4-(trifluoromethyl)-1,9a-dihydro-
2H-quinolizine-3-carboxylate (5k) Light yellow sol-
id, yield 65%. m.p. 152.1－152.9 ℃.
4h: 1H NMR (500 MHz, CDCl3) δ: 3.50 (s, 3H), 5.13
(s, 1H), 5.20－5.22 (m, 1H), 5.51 (s, 1H), 5.73－5.78
(m, 1H), 6.31－6.37 (m, 2H), 7.27－7.30 (m, 1H),
7.43－7.45 (m, 1H), 7.53－7.54 (m, 1H); 19F NMR
(470 MHz, CDCl3) δ: 59.5 (s, CF3).
5h: 1H NMR (500 MHz, CDCl3) δ: 3.59 (s, 3H), 4.58
(s, 1H), 5.12 (s, 1H), 5.31－5.33 (m, 1H), 5.73－5.78
(m, 1H), 6.31－6.37 (m, 1H), 6.62－6.64 (m, 1H),
7.17－7.18 (m, 1H), 7.27－7.30 (m, 1H), 7.53－7.54
(m, 1H); 19F NMR (470 MHz, CDCl3) δ: 59.5 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 41.6, 45.2, 47.0,
53.0, 57,3, 63.1, 101.9, 103.0, 111.0, 111.6, 119.7,
1
119.8 (q, JC-F＝276.5 Hz, CF3), 127.5, 127.8, 129.1,
2
131.6, 132.2, 133.6 (q, JC-F＝33.1 Hz, CF3), 134.0,
4k: 1H NMR (500 MHz, CDCl3) δ: 3.55 (s, 3H), 4.70
(s, 1H), 5.09 (d, J＝4.1 Hz, 1H), 5.21－5.23 (m, 1H),
5.73－5.76 (m, 1H), 6.32－6.37 (m, 2H), 7.61－7.63
(m, 2H), 8.28－8.30 (m, 2H); 19F NMR (470 MHz,
CDCl3) δ: 59.6 (s, CF3).
134.3, 164.3; IR (KBr) ν: 2911, 2406, 2368, 1712, 1629,
1274, 1181, 1163, 983, 734 cm1; MS (ESI) m/z: 454
[(M＋H)]＋. HRMS (ESI) calcd for C20H13Cl2F3N3O2
[(M＋H)]＋: 454.0331; found 454.0323.
cis-Methyl 1,1-dicyano-2-(2,4-dichlorophenyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4i) and trans-methyl 1,1-dicyano-
2-(2,4-dichlorophenyl)-4-(trifluoromethyl)-1,9a-
5k: 1H NMR (500 MHz, CDCl3) δ: 3.55 (s, 3H), 4.47
(s, 1H), 4.62－4.63 (m, 1H), 5.32－5.35 (m, 1H),
5.65－5.67 (m, 1H), 6.32－6.37 (m, 2H), 7.61－7.63
(m, 2H), 8.28－8.30 (m, 2H); 19F NMR (470 MHz,
CDCl3) δ: 59.3 (s, CF3).
dihydro-2H-quinolizine-3-carboxylate (5i)
solid, yield 51%. m.p. 156.4－157.2 ℃.
White
13C NMR (125 MHz, CDCl3) δ: 43.5, 51.1, 53.2,
54.5, 60.4, 62.5, 102.0, 111.0, 111.5, 111.7, 118.3,
4i: 1H NMR (500 MHz, CDCl3) δ: 3.52 (s, 3H), 5.12
(s, 1H), 5.20－5.22 (m, 1H), 5.38 (s, 1H), 5.72－5.78
(m, 1H), 6.30－6.36 (m, 2H), 7.31－7.33 (m, 1H), 7.45
1
119.8 (q, JC-F＝276.8 Hz, CF3), 124.2, 124.5, 127.6,
Chin. J. Chem. 2016, 34, 524—532
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
527

Shen et al.
FULL PAPER
2
129.0, 129.9, 130.2, 134.2 (q, JC-F＝34.7 Hz, CF3),
138.7, 148.9, 164.6; IR (KBr) ν: 2912, 2356, 2166, 1732,
1638, 1527, 1351, 1264, 1189, 1150, 988 cm1; MS
(ESI) m/z: 431 [(M＋H)]＋ . HRMS (ESI) calcd for
C20H14F3N4O4 [(M＋H)]＋: 431.0962; found 431.0955.
cis-Methyl 1,1-dicyano-2-(3-nitrophenyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4l) and trans-methyl 1,1-dicyano-
2-(3-nitrophenyl)-4-(trifluoromethyl)-1,9a-dihydro-
2H-quinolizine-3-carboxylate (5l) Light yellow solid,
yield 41%. m.p. 149.7－150.6 ℃.
id, yield 48%. m.p. 145.2－145.9 ℃.
4n: 1H NMR (500 MHz, CDCl3) δ: 3.61 (s, 3H), 4.60
(s, 1H), 5.08 (d, J＝4.5 Hz, 1H), 5.20－5.23 (m, 1H),
5.72－5.75 (m, 1H), 6.31－6.36 (m, 2H), 7.55－7.61
(m, 1H), 7.64－7.65 (m, 2H), 7.74－7.76 (m, 1H); 19F
NMR (470 MHz, CDCl3) δ: 59.6 (s, CF3).
5n: 1H NMR (500 MHz, CDCl3) δ: 3.61 (s, 3H), 4.40
(s, 1H), 4.61 (s, 1H), 5.33－5.35 (m, 1H), 5.66－5.67
(m, 1H), 6.31－6.36 (m, 1H), 6.62－6.64 (m, 1H),
7.55－7.60 (m, 3H), 7.74－7.76 (m, 1H); 19F NMR
(470 MHz, CDCl3) δ: 59.3 (s, CF3).
4l: 1H NMR (500 MHz, CDCl3) δ: 3.54 (s, 3H), 4.70
(s, 1H), 5.10 (d, J＝4.1 Hz, 1H), 5.22－5.23 (m, 1H),
5.73－5.76 (m, 1H), 6.33－6.37 (m, 2H), 7.63－7.67
(m, 1H), 7.78－7.80 (m, 1H), 8.30－8.31 (m, 2H); 19F
NMR (470 MHz, CDCl3) δ: 59.6 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 43.6, 51.0, 53.1,
62.5, 101.9, 111.1, 111.6, 111.8, 113.4, 117.8, 118.4,
1
119.8 (q, JC-F＝276.7 Hz, CF3), 127.5, 129.0, 130.1,
132.5, 133.3, 133.8, 134.0 (q, JC-F＝34.5 Hz, CF3),
164.6; IR (KBr) ν: 2930, 2330, 2236, 1735, 1639, 1586,
1260, 1189, 1143, 878, 706 cm1; MS (ESI) m/z: 411
[(M＋H)]＋. HRMS (ESI) calcd for C21H14F3N4O2 [(M
＋H)]＋: 411.1063; found 411.1056.
2
5l: 1H NMR (500 MHz, CDCl3) δ: 3.60 (s, 3H), 4.48
(s, 1H), 4.62－4.63 (m, 1H), 5.34－5.35 (m, 1H), 5.67
－5.68 (m, 1H), 6.33－6.37 (m, 1H), 6.63－6.64 (m,
1H), 7.63－7.67 (m, 2H), 8.19－8.21 (m, 1H), 8.30－
8.31 (m, 1H); 19F NMR (470 MHz, CDCl3) δ: 59.4 (s,
CF3).
cis-Methyl 1,1-dicyano-4-(trifluoromethyl)-
2-(4-(trifluoromethyl)phenyl)-1,9a-dihydro-2H-
quinolizine-3-carboxylate (4o) and trans-methyl 1,1-
dicyano-4-(trifluoromethyl)-2-(4-(trifluoromethyl)
phenyl)-1,9a-dihydro-2H-quinolizine-3-carboxylate
(5o) Light yellow solid, yield 55%. m.p. 134.6－
135.2℃.
13C NMR (125 MHz, CDCl3) δ: 40.9, 43.6, 51.0,
53.2, 62.5, 101.9, 111.1, 111.5, 111.7, 118.3, 119.8 (q,
1JC-F＝276.6 Hz, CF3), 124.2, 125.1, 127.5, 129.0, 130.3,
2
133.7, 134.1 (q, JC-F＝34.9 Hz, CF3), 134.8, 148.4,
164.6; IR (KBr) ν: 2959, 2371, 2249, 1728, 1648, 1584,
4o: 1H NMR (500 MHz, CDCl3) δ: 3.53 (s, 3H), 4.64
(s, 1H), 5.08 (d, J＝4.3 Hz, 1H), 5.19－5.21 (m, 1H),
5.72－5.75 (m, 1H), 6.31－6.35 (m, 2H), 7.55－7.56
(m, 2H), 7.68－7.70 (m, 2H); 19F NMR (470 MHz,
CDCl3) δ: 62.9 (s, CF3), 59.6 (s, CF3).
1533, 1352, 1305, 1193, 1146, 982 [M]＋. HRMS (EI)
＋
calcd for C20H13F3N4O4 [M] : 430.0889; found
430.0891.
cis-Methyl 1,1-dicyano-2-(4-cyanophenyl)-
4-(trifluoromethyl)-2,9a-dihydro-1H-quinolizine-3-
carboxylate (4m) and trans-methyl 1,1-dicyano-
2-(4-cyanophenyl)-4-(trifluoromethyl)-2,9a-dihydro-
5o: 1H NMR (500 MHz, CDCl3) δ: 3.60 (s, 3H), 4.44
(s, 1H), 4.63－4.64 (s, 1H), 5.32－5.34 (m, 1H), 5.65－
5.67 (m, 1H), 6.31－6.35 (m, 1H), 6.61－6.63 (m, 1H),
7.46－7.47 (m, 2H), 7.68－7.70 (m, 2H); 19F NMR
(470 MHz, CDCl3) δ: 62.9 (s, CF3), 59.3 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 43.7, 51.4, 53.1,
1H-quinolizine-3-carboxylate (5m)
solid, yield 67%. m.p. 142.6－143.6 ℃.
Light yellow
4m: 1H NMR (500 MHz, CDCl3) δ: 3.54 (s, 3H),
4.63 (s, 1H), 5.07 (d, J＝4.0 Hz, 1H), 5.20－5.22 (m,
1H), 5.72－5.75 (m, 1H), 6.30－6.36 (m, 2H), 7.54－
7.56 (m, 2H), 7.72－7.74 (m, 2H); 19F NMR (470 MHz,
CDCl3) δ: 59.6 (s, CF3).
1
62.7, 101.8, 111.1, 111.7, 118.9, 119.8 (q, JC-F＝276.6
Hz, CF3), 123.6 (q, 1JC-F＝276.6 Hz, CF3), 126.1, 127.5,
2
129.1, 129.5, 132.3 (q, JC-F＝34.9 Hz, CF3), 133.8 (q,
2JC-F＝34.9 Hz, CF3), 135.4, 164.7; IR (KBr) ν: 2957,
2369, 2232, 1717, 1639, 1588, 1326, 1147, 1126, 1069,
850 cm1; MS (EI) m/z: 453 [M]＋. HRMS (EI) calcd for
C21H13F6N3O2 [M]＋: 453.0912; found 453.0917.
5m: 1H NMR (500 MHz, CDCl3) δ: 3.60 (s, 3H),
4.42 (s, 1H), 4.58－4.59 (m, 1H), 5.32－5.34 (m, 1H),
5.64－5.66 (m, 1H), 6.30－6.36 (m, 1H), 6.59－6.62
(m, 1H), 7.47－7.48 (m, 2H), 7.72－7.74 (m, 2H); 19F
NMR (470 MHz, CDCl3) δ: 59.3 (s, CF3).
cis-Methyl 1,1-dicyano-2-(4-fluorophenyl)-4-
(trifluoromethyl)-2,9a-dihydro-1H-quinolizine-3-
carboxylate (4p) and trans-methyl 1,1-dicyano-
2-(4-fluorophenyl)-4-(trifluoromethyl)-2,9a-dihydro-
1H-quinolizine-3-carboxylate (5p): Light yellow solid,
yield 88%. m.p. 150.0－150.8 ℃.
13C NMR (125 MHz, CDCl3) δ: 43.6, 51.5, 53.2,
62.6, 101.9, 111.1, 111.7, 114.2, 116.4, 118.4, 119.8 (q,
1JC-F＝277.6 Hz, CF3), 127.6, 129.0, 129.9, 132.8, 133.1,
134.1 (q, 2JC-F＝33.8 Hz, CF3), 136.8, 164.6; IR (KBr) ν:
2961, 2371, 2232, 1741, 1637, 1585, 1256, 1183, 1141,
4p: 1H NMR (500 MHz, CDCl3) δ: 3.53 (s, 3H), 4.55
(s, 1H), 5.06 (d, J＝4.5 Hz, 1H), 5.16－5.19 (m, 1H),
5.71－5.73 (m, 1H), 6.29－6.33 (m, 2H), 7.09－7.12
(m, 2H), 7.40－7.42 (m, 2H); 19F NMR (470 MHz,
CDCl3) δ: 110.3－110.2 (m, F), 59.6 (s, CF3).
5p: 1H NMR (500 MHz, CDCl3) δ: 3.59 (s, 3H), 4.36
(m, 1H), 4.59－4.60 (m, 1H), 5.29－5.32 (m, 1H), 5.66
－5.67 (m, 1H), 6.30－6.33 (m, 1H), 6.61－6.62 (m,
1H), 7.09－7.11 (m, 2H), 7.28－7.29 (m, 2H); 19F NMR
984, 733 cm1; MS (EI) m/z: 410 [M]＋. HRMS (EI)
＋
calcd for C21H13F3N4O2 [M] : 410.0991; found
410.0998.
cis-Methyl 1,1-dicyano-2-(3-cyanophenyl)-
4-(trifluoromethyl)-1,9a-dihydro-2H-quinolizine-3-
carboxylate (4n) and trans-methyl 1,1-dicyano-
2-(3-cyanophenyl)-4-(trifluoromethyl)-1,9a-dihydro-
2H-quinolizine-3-carboxylate (5n) Light yellow sol-
528
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 524—532

An Efficient One-pot Three-component Process for Synthesis of Perfluoroalkylated Quinolizines
(470 MHz, CDCl3) δ: 110.3－110.2 (m, F), 59.3 (s,
CF3).
2953, 2373, 2224, 1739, 1628, 1584, 1250, 1219, 1094,
984, 735 cm1; MS (ESI) m/z: 470 [(M＋ H)]＋. HRMS
(ESI) calcd for C21H14ClF5N3O2 [(M＋H)]＋: 407.0689;
found 407.0688.
13C NMR (125 MHz, CDCl3) δ: 41.8, 44.1, 47.6,
51.0, 52.9, 56.6, 58.3, 62.6, 101.6, 103.0, 111.4, 111.8,
1
111.9, 116.2, 116.3, 119.6, 119.9 (q, JC-F＝280.0 Hz,
cis-Methyl 1,1-dicyano-4-(pentafluoroethyl)-
2-(p-tolyl)-2,9a-dihydro-1H-quinolizine-3-carboxylate
(4s) and trans-methyl 1,1-dicyano-4-(pentafluoro
ethyl)-2-(p-tolyl)-2,9a-dihydro-1H-quinolizine-3-
carboxylate (5s) Light yellow solid, yield 50%. m.p.
153.7－154.6 ℃.
2
CF3), 126.9, 127.4, 129.1, 131.0, 133.2 (q, JC-F＝34.4
Hz, CF3), 162.6, 164.8; IR (KBr) ν: 2960, 2356, 2251,
1730, 1639, 1587, 1264, 1178, 1104, 734 cm1; MS (EI)
m/z: 403 [M]＋. HRMS (EI) calcd for C20H13F4N3O2
[M]＋: 403.0944; found 403.0950.
4s: 1H NMR (500 MHz, CDCl3) δ: 2.36 (s, 3H), 3.50
(s, 3H), 4.46－4.70 (m, 1H), 4.92－4.93 (m, 1H), 5.17
－5.20 (m, 1H), 5.67－5.73 (m, 1H), 6.30－6.37 (m,
1H), 6.40－6.41 (m, 1H), 7.20－7.22 (m, 3H), 7.28－
7.30 (m, 2H); 19F NMR (470 MHz, CDCl3) δ: 111.3－
103.9 (m, CF2), 80.2 (s, CF3).
cis-Methyl 1,1-dicyano-2-(4-(methoxycarbonyl)
phenyl)-4-(trifluoromethyl)-2,9a-dihydro-1H-
quinolizine-3-carboxylate (4q) and trans-methyl
1,1-dicyano-2-(4-(methoxycarbonyl)phenyl)-4-
(trifluormethyl)-2,9a-dihydro-1H-quinolizine-3-
carboxylate (5q) Light yellow solid, yield 68%. m.p.
184.2－185.4 ℃.
5s: 1H NMR (500 MHz, CDCl3) δ: 2.36 (s, 3H), 3.50
(s, 3H), 4.31－4.32 (m, 1H), 4.46－4.47 (m, 1H), 4.49
－4.50 (m, 1H), 5.25－5.28 (m, 1H), 5.67－5.73 (m,
1H), 6.30－6.37 (m, 1H), 6.72－6.74 (m, 1H), 7.11－
7.13 (m, 2H), 7.20－7.22 (m, 2H); 19F NMR (470 MHz,
CDCl3) δ: 109.4－103.6 (m, CF2), 81.4 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 21.9, 43.4, 50.6,
4q: 1H NMR (500 MHz, CDCl3) δ: 3.50 (s, 3H), 3.92
(s, 3H), 4.63 (m, 1H), 5.07 (d, J＝4.5 Hz, 1H), 5.17－
5.20 (m, 1H), 5.72－5.74 (m, 1H), 6.31－6.34 (m, 2H),
7.49－7.50 (m, 2H), 8.07－8.09 (m, 2H); 19F NMR (470
MHz, CDCl3) δ:59.6 (s, CF3).
5q: 1H NMR (500 MHz, CDCl3) δ: 3.56 (s, 3H), 3.92
(s, 3H), 4.42 (s, 1H), 4.63 (s, 1H), 5.31－5.32 (s, 1H),
5.65－5.67 (m, 1H), 6.31－6.34 (m, 1H), 6.61－6.63
(m, 1H), 7.39－7.40 (m, 2H), 8.07－8.09 (m, 2H); 19F
NMR (470 MHz, CDCl3) δ: 59.3 (s, CF3).
1
53.1, 60.9, 80.3, 111.3 (tq, JC-F＝258.6 Hz, 2JC-F＝38.6
1
Hz, CF2), 113.0, 113.9, 114.8, 118.7 (qt, JC-F＝286.8
Hz, 2JC-F＝36.4 Hz, CF3), 129.2, 129.7, 130.2, 130.6 (t,
2JC-F＝24.7 Hz, CF2), 131.2, 131.4, 132.6, 146.1, 161.7;
IR (KBr) ν: 2919, 2312, 2226, 1794, 1626, 1587, 1248,
1153, 1016, 875 cm1; MS (ESI) m/z: 450 [(M＋H)]＋.
HRMS (ESI) calcd for C22H18F5N3O2 [(M ＋ H)] ＋ :
450.1235; found 450.1230.
13C NMR (125 MHz, CDCl3) δ: 43.7, 51.5, 52.4,
1
53.0, 62.6, 101.7, 111.2, 111.8, 119.3, 119.9 (q, JC-F
＝
276.1 Hz, CF3), 127.5, 129.2, 130.3, 131.8, 133.2, 133.6
(q, 2JC-F＝34.6 Hz, CF3), 164.7, 166.2; IR (KBr) ν: 2947,
2366, 2253, 1724, 1645, 1585, 1286, 1252, 1192, 1144,
1113, 979, 732 cm1; MS (EI) m/z: 443 [M]＋. HRMS
(EI) calcd for C22H16F3N3O4 [M]＋: 443.1093; found
443.1090.
cis-Methyl 2-(4-chlorophenyl)-1,1-dicyano-4-
(n-heptafluoropropyl)-2,9a-dihydro-1H-quinolizine-
3-carboxylate (4t) and trans-methyl 2-(4-chloro-
phenyl)-1,1-dicyano-4-(n-heptafluoropropyl)-2,9a-
cis-Methyl 2-(4-chlorophenyl)-1,1-dicyano-4-
(pentafluoroethyl)-2,9a-dihydro-1H-quinolizine-3-
carboxylate (4r) and trans-methyl 2-(4-chlorophenyl)-
1,1-dicyano-4-(pentafluoroethyl)-2,9a-dihydro-1H-
quinolizine-3-carboxylate (5r) Light yellow solid,
yield 56%. m.p. 157.4－158.2 ℃.
dihydro-1H-quinolizine-3-carboxylate (5t)
yellow solid, yield 48%. m.p. 127.9－128.8 ℃.
Light
4t: 1H NMR (500 MHz, CDCl3) δ: 3.53 (s, 3H), 4.51
－4.52 (m, 1H), 4.93－4.94 (m, 1H), 5.22－5.25 (m,
1H), 5.74－5.76 (m, 1H), 6.34－6.49 (m, 1H), 6.77－
6.79 (m, 1H), 7.38－7.44 (m, 4H); 19F NMR (470 MHz,
CDCl3) δ: 122.3 (s, CF2), 109.1－101.7 (m, CF2),
80.6－80.2 (m, CF3).
4r: 1H NMR (500 MHz, CDCl3) δ: 3.52 (s, 3H), 4.49
(s, 1H), 4.94 (d, J＝4.0 Hz, 1H), 5.19－5.22 (m, 1H),
5.68－5.74 (m, 1H), 6.32－6.41 (m, 2H), 7.35－7.41
(m, 4H); 19F NMR (470 MHz, CDCl3) δ: 111.3－
103.9 (m, CF2), 80.2 (s, CF3).
5t: 1H NMR (500 MHz, CDCl3) δ: 3.53 (s, 3H), 4.37
－4.38 (m, 1H), 4.44－4.45 (m, 1H), 5.31－5.33 (m,
1H), 5.74－5.76 (m, 1H), 6.34－6.49 (m, 1H), 6.77－
6.79 (m, 1H), 7.22－7.24 (m, 2H), 7.38－7.44 (m, 2H);
19F NMR (470 MHz, CDCl3) δ: 124.0－121.9 (m,
CF2), 107.5－100.3 (m, CF2), 80.2－80.1 (m, CF3).
13C NMR (125 MHz, CDCl3) δ: 44.1, 48.7, 50.7,
52.3, 52.9, 57.5, 60.4, 62.8, 102.7, 103.4, 109.0 (m,
CF2), 111.5, 111.8, 112.4, 112.7, 112.9 (m, CF2), 113.5,
5r: 1H NMR (500 MHz, CDCl3) δ: 3.52 (s, 3H), 4.34
(s, 1H), 4.44－4.45 (m, 1H), 5.29－5.30 (m, 1H),
5.68－5.74 (m, 1H), 6.32－6.41 (m, 1H), 6.73－6.74
(m, 1H), 7.19－7.21 (m, 2H), 7.35－7.41 (m, 2H); 19F
NMR (470 MHz, CDCl3) δ: 109.3－103.6 (m, CF2),
81.4 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 42.1, 44.0, 48.6,
52.2, 53.0, 57.5, 60.4, 62.8, 102.6, 103.4, 111.1 (tq, 1JC-F
＝259.8 Hz, 2JC-F＝39.5 Hz, CF2), 111.4, 111.7, 111.8,
112.7, 113.5, 118.5 (qt, 1JC-F＝286.6 Hz, 2JC-F＝35.9 Hz,
CF3), 124.8, 127.5, 129.3, 130.1 (t, 2JC-F＝24.3 Hz, CF2),
130.7, 131.5, 131.9, 136.3, 158.4, 164.7; IR (KBr) ν:
1
114.3 117.5 (qt, JC-F＝286.4 Hz, 2JC-F＝33.9 Hz, CF3),
2
127.5, 130.1 (t, JC-F＝24.8 Hz, CF2), 130.8, 131.9,
141.1, 158.4; IR (KBr) ν: 2914, 2370, 2340, 1741, 1627,
1586, 1223, 1115, 742 cm1; MS (ESI) m/z: 520 [(M＋
H)]＋. HRMS (ESI) calcd for C22H14ClF7N3O2 [(M＋H)]＋:
Chin. J. Chem. 2016, 34, 524—532
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
529

Shen et al.
FULL PAPER
520.0591; found 520.0665.
cis-Methyl 1,1-dicyano-4-(n-heptafluoropropyl)-
2-(p-tolyl)-2,9a-dihydro-1H-quinolizine-3-carboxylate
(4u) and trans-methyl 1,1-dicyano-4-(n-hepta-
fluoroprpyl)-2-(p-tolyl)-2,9a-dihydro-1H-quinolizine-
3-carboxylate (5u) Light yellow solid, yield 45%. m.p.
124.3－125.1 ℃.
4u: 1H NMR (500 MHz, CDCl3) δ: 2.31 (s, 3H), 3.48
(s, 3H), 4.47 (s, 1H), 4.90－4.91 (m, 1H), 5.17－5.19
(m, 1H), 5.68－5.73 (m, 1H), 6.30－6.37 (m, 1H), 6.44
－6.46 (m, 1H), 7.20－7.21 (m, 4H); 19F NMR (470
MHz, CDCl3) δ: 122.5 (s, CF2), 108.7－100.9 (m,
CF2), 80.3－80.2 (m, CF3).
1
5u: H NMR (500 MHz, CDCl3) δ: 2.31 (s, 3H),
3.48 (s, 3H), 4.33－4.34 (s, 1H), 4.47 (s, 1H), 5.26－
5.28 (m, 1H), 5.68－5.73 (m, 1H), 6.30－6.37 (m, 1H),
6.73－6.75 (m, 1H), 7.12－7.13 (m, 2H), 7.27－7.29 (m,
2H); 19F NMR (470 MHz, CDCl3) δ: 123.9－121.6 (m,
CF2), 107.3－99.3 (m, CF2), 80.3－80.2 (s, CF3).
13C NMR (125 MHz, CDCl3) δ: 21.9, 43.5, 50.8,
53.1, 61.0, 109.3 (m, CF2), 112.3, 113.0, 113.8, 114.3
Hb
N
CF3
Ha
NC
NC
CO2CH3
1
(m, CF2), 114.8, 117.7 (qt, JC-F＝284.6 Hz, 2JC-F＝30.1
2
Hz, CF3), 129.2, 129.7, 130.6, 131.2 (t, JC-F＝26.7 Hz,
CF2), 146.1, 161.7; IR (KBr) ν: 2924, 2372, 2222, 1747,
1628, 1587, 1219, 1152, 1111, 875 cm1; MS (ESI) m/z:
500 [(M＋H)]＋. HRMS (ESI) calcd for C22H17F3N3O4
[(M＋H)]＋: 500.1142; found 500.1215.
Figure 2 NOESY spectrum of compounds 4a and 5a.
Table 1 Optimization of the reaction conditionsa
CF3
CN
Results and Discussion
+
+
CN
N
CO2Me
Initially, a mixture of pyridine 2 (1.5 mmol),
2-benzylidenemalononitrile (1a) (1.0 mmol) and methyl
4,4,4-trifluorobut-2-ynoate (3a) (2.0 mmol) was stirred
in acetonitrile (3.0 mL) at room temperature for 1.0 h.
Two diastereomeric compounds 4a and 5a were ob-
tained in 50% total yield (Table 1, Entry 3).
1a
2
3a
H
H
N
H
CF3
N
H
CF3
NC
NC
NC
NC
CO2Me
+
CO2Me
The structure of the quinolizine derivative 4a was
confirmed by single-crystal X-ray analysis (Figure 1).[8]
According to the interaction signals between Ha and Hb
in NOESY spectra (Figure 2), the configuration of dia-
stereomer 4a was also established.
4a
5a
Entry Solvent
T/℃
t/h
1∶2∶3
Yieldb/%
1
2
3
4
5
6
7
8
9
CH2Cl2
THF
25
25
25
25
25
25
0
1
1
1
1
1
1
1
1
1
1
1.0∶1.0∶1.2
1.0∶1.0∶1.2
1.0∶1.0∶1.2
1.0∶1.0∶1.2
1.0∶1.0∶1.2
1.0∶1.0∶1.2
1.0∶1.0∶1.2
1.0∶1.0∶1.2
1.0∶1.0∶1.2
1.0∶1.5∶2.0
33
42
50
48
－
35
67
68
45
82
83
77
MeCN
Acetone
EtOH
Toluene
MeCN
MeCN
MeCN
10
80
0
10
11
MeCN
MeCN
MeCN
0
0.5 1.0∶1.5∶2.0
1.0∶1.5∶2.0
12
0
2
a
Reaction conditions: pyridine 2 (1.5 mmol), 2-benzylidene-
malononitrile 1a (1.0 mmol) and methyl 4,4,4-trifluorobut-
2-ynoate (3a) (2.0 mmol), solvent 3.0 mL. b Total isolated yield of
4a and 5a.
Figure 1 X-ray structure of compound 4a.
530
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 524—532

An Efficient One-pot Three-component Process for Synthesis of Perfluoroalkylated Quinolizines
Table 2 Scope for the synthesis of perfluoroalkylated quinolizinesa
H
H
N
H
RF
RF
N
H
RF
CH3CN, 0 oC
30 min
CN
NC
NC
NC
NC
CO2Me
+
+
+
R
CO2Me
CN
N
CO2Me
1
2
3
R
R
4
5
Entry
R
Perfluoroalkynoate 3
Products 4 and 5
Ratio (4∶5)
Yieldb/%
1
1
2
H
1a
1b
1c
1d
1e
1f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
4a＋5a
4b＋5b
4c＋5c
4d＋5d
4e＋5e
4f＋5f
4g＋5g
4h＋5h
4i＋5i
6∶1
6∶1
5∶1
3∶1
7∶1
6∶1
3∶1
3∶1
3∶:1
3∶1
10∶1
8∶1
12∶1
9∶1
－
81
82
84
80
85
78
57
50
51
64
65
41
67
48
－
55
88
68
56
50
48
45
4-Me
3-Me
2-Me
4-Cl
3-Cl
2-Cl
3
4
5
6
7
1g
1h
1i
8
2,3-Dichloro
2,4-Dichloro
2,3-Dimethyl
4-NO2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1j
4j＋5j
4k＋5k
4l＋5l
1k
1l
3-NO2
4-CN
1m
1n
1r
1o
1p
1q
1e
1b
1e
1b
4m＋5m
4n＋5n
－
3-CN
4-OMe
4-CF3
4o＋5o
4p＋5p
4q＋5q
4r＋5r
4s＋5s
4t＋5t
4u＋5u
8∶1
7∶1
9∶1
2.6∶1
2.6∶1
2∶1
2∶1
4-F
4-CO2Me
4-Cl
4-Me
4-Cl
4-Me
a Reaction conditions: pyridine 2 (1.5 mmol), arylidenemalononitriles 1 (1.0 mmol) and methyl perfluoroalk-2-ynoates 3 (2.0 mmol) were
stirred in acetonitrile (3.0 mL) at 0 ℃ for 0.5 h. b Total isolated yield of 4 and 5.
Encouraged by the above result, we used the
three-component reaction of pyridine 2, 2-benzylidene-
malononitrile (1a) and methyl 4,4,4-trifluorobut-2-yno-
ate (3a) as model substrates to optimize the reaction
conditions. As shown in Table 1, acetonitrile was found
to be the most appropriate solvent (Table 1, Entries 1－
6). And temperature was found to have an obvious in-
fluence on the reaction yield (Table 1, Entries 7－9).
The suitable temperature is 0 ℃. Besides, similar re-
sults could be obtained when the reaction time was
shortened to 0.5 h (Table 1, Entry 11). Therefore, the
best result (83% yield) was obtained in acetonitrile at
0 ℃ for 0.5 h.
drawing or electron-donating groups on the aromatic
ring worked well under standard conditions, affording
diastereomeric mixtures of the corresponding quinoliz-
ines in moderate to good yields. Electron-rich arylidene-
malononitriles gave higher yield than electron-deficient
ones. Substantial steric hindrance was tolerated on the
aromatic ring at the para-, meta-, and ortho-positions
with the slightly decreasing of the total yield and the
lowering ratio of the major isomer 4 in diastereomeric
mixture (Table 2, Entry 2 vs. 3 vs. 4, and Entry 5 vs. 6
vs. 7). With the number of carbon atoms of methyl per-
fluoroalk-2-ynoates 3 increasing, both the total yield of
the product and the ratio of the major diastereomer 4
decreased. If substituted pyridines were used as starting
materials, the reaction system became complicated and
no desired product was obtained.
Having established the optimized conditions, the
scope and generality of the present method were ex-
plored and the results were summarized in Table 2.
Various arylidenemalononitriles with electron-with-
Based on the experimental results and previous re-
Chin. J. Chem. 2016, 34, 524—532
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
531

Shen et al.
FULL PAPER
ports,[3a,3c] a plausible mechanism was illustrated in
Scheme 1. The reaction occurred through the process of
the initial formation of 1,4-dipolar intermediate (6) from
pyridine 2 and methyl 4,4,4-trifluorobut-2-ynoate (3a)
followed by its trapping of 2-benzylidenemalononitrile
1a to generate intermediate 7. Intramolecular ring clo-
sure of the latter yielded 4a and 5a.
(b) Steven, J. C.; Annika, S.; Peter, O. B. Tetrahedron 2014, 70,
7395; (c) Lei, B. T.; Ma, C. Y. Tradition Chin. Med. 2014, 32, 254;
(d) Joseph, P. M. Nat. Prod. Rep. 2001, 18, 520; (e) Ji, H. K.; Eun,
B. C.; Lee, J.; Sang, Y. L. Chemico-Biological Interactions 2015,
242, 25.
[2] (a) Xu, Y. S.; Zeng, C. C.; Jiao, Z. G.; Hu, L. M.; Zhong, R. Mole-
cules 2009, 14, 868; (b) Katsumasa, K.; Jun, H.; Shinichi, K.; Mas-
anobu, K. Jpn. J. Pharmacol. 1993, 63, 73; (c) Parhi, A.; Lu, S.;
Kelley, C.; Kaul, M.; Daniel, S. P. Bioorg. Med. Chem. Lett. 2012,
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Res. 2011, 31, 921; (f) Francesca, A.; Fedele, M.; Cosimo, P.; Maria,
L. S. J. Med. Chem. 1975, 18, 1145; (g) Ma, H.; Hu, Y. R.; Zou, Z.
Y.; Wang, D. Z.; Ye, X. L.; Li, X. G. Chin. Pharmacol. Bull. 2015,
31, 1575; (h) Gong, S.; Sun, J. M.; Tian, L. L.; Zhang, H. Jilin J.
Traditional Chin. Med. 2014, 34, 927.
[3] (a) Vijay, N. B.; Rema, D.; Luxmi, R. V. Tetrahedron Lett. 2005, 46,
5333; (b) Vijay, N.; Devipriya, S.; Eringathodi, S. Tetrahedron 2008,
64, 3567; (c) Abbas, A. E.; Farzaneh, Z.; Abbas, M.; Mohammad, I.;
Ali, R. F. Tetrahedron Lett. 2014, 55, 333; (d) He, H.; Qi, C.; Ou, Y.
L. Org. Biomol. Chem. 2014, 12, 8128.
Scheme 1 Mechanism for the formation of products 4a and 5a
NC
NC
Ph
1a
CF3
N
CO2Me
N
CO2Me
CF3
2
3a
6
H
H
N
CF3
CO2Me
N
CF3
N
H
CF3
+
H
NC
NC
NC
NC
NC
CO2Me NC
[4] (a) Xin, Y.; Zhao, J.; Zhu, S. J. Fluorine Chem. 2012, 133, 97; (b)
Song, Y.; Han, X.; Wang, Z. WO 2015/173164 A1.
CO2Me
Ph
Ph
Ph
7
[5] (a) Cao, L.; Shen, D.; Wei, J.; Chen, J.; Zhang, H.; Cao, W. Eur. J.
Org. Chem. 2014, 2460; (b) Han, J.; Cao, L.; Bian, L.; Chen, J.;
Zhang, H.; Cao, W. Adv. Synth. Catal. 2013, 355, 1345; (c) Wei, J.;
Chen, J.; Xu, J.; Cao, L.; Cao, W. J. Fluorine Chem. 2012, 133, 146;
(d) Yu, H.; Han, J.; Chen, J.; Zhang, H.; Cao, W. Eur. J. Org. Chem.
2012, 3142; (e) Xu, J.; Wei, J.; Bian, L.; Chen, J.; Zhang, H.; Cao,
W. Chem. Commun. 2011, 47, 3607; (f) Lu, L.; Cao, W.; Chen, J.;
Zhang, H. J. Fluorine Chem. 2009, 130, 295; (g) Lu, L.; Wei, J.;
Chen, J.; Zhang, H.; Cao, W. Tetrahedron 2009, 65, 9152.
[6] (a) Gregory, B. K.; Emi, H.; Jamie, L.; Amanda, P. M. J. Macromol.
Sci. 2008, 45, 420; (b) Wang, X. S.; Zeng, Z. S.; Li, Y. L.; Shi, D.;
Tu, S. J. Synth. Commun. 2005, 35, 1915; (c) Zhu, F.; Sun, X.; Lou,
F. Catal. Lett. 2015, 145, 1072; (d) Gregory, B. K.; Selena, M. R.;
Robert, C.; Tess, L. C.; Erika, A. C. J. Macromol. Sci. 2008, 45, 261;
(e) Gregory, B. K.; Selena, M. R.; Aisha, A.; Michael, L. J.; Aishek,
P. R. J. Macromol. Sci. 2008, 45, 416; (f) Feroci, M.; Sotgiu, G.;
Orsini, M. Electrochim. Acta 2008, 53, 2346; (g) Brunskil1, J. S.; Oe,
A. Synth. Commun. 1978, 8, 1; (h) Andr, P.; Michael, S. H.; Bernd,
P. Chem. Eur. J. 2012, 18, 2423.
5a
4a
Conclusions
In summary, we have developed a facile one-pot
process for synthesis of perfluoroalkylated quinolizines
4 and 5. This method has the advantage of mild condi-
tion, moderate yields of product, easy operation and
short reaction time. Moreover, all the starting materials
are simple and readily available. Further synthetic ap-
plications of perfluoroalkylated quinolizines compounds
are still being investigated in our laboratory.
Acknowledgement
The authors are grateful to the National Natural Sci-
ence Foundation of China (Grant Nos. 21542005,
21272152), Yang Fan Program of Science and Technol-
ogy Commission of Shanghai Municipality (Grant No.
15YF1404200) and Shanghai Municipal Education
Commission (Peak Discipline Construction Program)
for their financial support.
[7] (a) Hamper, B. C. J. Org. Chem. 1988, 53, 5558; (b) Hamper, B. C.
Org. Synth. 1992, 70, 246.
[8] CCDC 1044054 (4a) contains all crystallographic details of this
publication
and
is
available
free
of
charge
at
www.ccdc.cam.ac.uk/consts/retrieving.html or can be ordered from
the following address: Cambridge Crystallographic Data Centre, 12
Union Road, GB-Cambridge CB21EZ; fax: (＋44)-1223-336-033;
or deposit@ccdc.cam.ac.uk. Unit cell parameters (4a): a＝13.647(5)
Å, b＝8.613(3) Å, c＝16.549(6) Å, α＝90°, β＝90°, γ＝90°, space
group: P21/n.
References
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(Pan, B.; Qin, X.)
532
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 524—532