From CO2 to 4 H-Quinolizin-4-ones: A One-Pot Multicomponent Approach via Ag2O/Cs2CO3 Orthogonal Tandem Catalysis

Article abstract of DOI:10.1021/acs.joc.8b01206

Using carbon dioxide as a C1 precursor, here we report relatively simple and cost-effective orthogonal tandem catalysis, namely Ag₂O in conjunction with Cs₂CO₃ serves to promote a multicomponent tandem reaction forming two new C-C and one new C-N bonds. 4H-Quinolizin-4-ones, key skeletal components in a variety of biologically active molecules, were obtained with yields up to 99%. The present approach features a broad substrate scope and mild reaction conditions and benefits from using cost-effective reaction and catalysts.

Full text of DOI:10.1021/acs.joc.8b01206

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Note
From CO2 to 4H-quinolizin-4-ones # A one pot multi-component
approach via Ag2O/Cs2CO3 orthogonal tandem catalysis
Chao-Chen Dong, Jun-Feng Xiang, Li-Jin Xu, and Han-Yuan Gong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01206 • Publication Date (Web): 06 Jun 2018
Downloaded from http://pubs.acs.org on June 8, 2018
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The Journal of Organic Chemistry
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From CO2 to 4H-quinolizin-4-ones ： A one pot multi-
component approach via Ag2O/Cs2CO3 orthogonal tandem ca-
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talysis
†
ChaoꢀChen Dong, JunꢀFeng Xiang, ǁ§ LiꢀJin Xu,* ‡ and HanꢀYuan Gong*†
‡
†College of Chemistry, Beijing Normal University, Beijing, 100875, P. R. China
‡Department of Chemistry, Renmin University of China, Beijing, 100872, P. R. China
ǁBeijing National Laboratory for Molecular Sciences (BNLMS), Institute of Chemistry, Chinese Academy of Sciences, Beiꢀ
jing, 100190, P. R. China.
§University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
Supporting Information Placeholder
ABSTRACT: Using carbon dioxide as C1 precursor, here we report relatively simple and costꢀeffective orthogonal tandem catalyꢀ
sis, namely Ag2O in conjunction with Cs2CO3 serves to promote a multiꢀcomponent tandem reaction forming two new CꢀC and one
new CꢀN bonds. 4Hꢀquinlizinꢀ4ꢀones, key skeletal components in a variety of biologically active molecules, were obtained with
yields up to 99%. The present approach features a broad substrate scope, mild reaction conditions, and benefits from using costꢀ
effective reaction and catalysts.
Orthogonal tandem catalysis (OTC) is one of the most atꢀ
tractive strategy for complex molecular construction. It is the
Scheme 1. Synthetic methods to 4H-quinolizin-4-ones.
methodology simultaneously using multiple catalysts in a oneꢀ
pot reaction to produce a final product, through sequential
mechanistically distinct reaction steps.1 Surprisingly, the exꢀ
amples of OTC for carbon dioxide (CO2) chemical fixation are
still lacking.2 CO2 has been considered as a compelling C1
precursor for the synthesis of premium chemicals, including
potential pharmaceutical agents, since it is abundant, readily
available, and environmentally benign.3 Despite significant
advances of CO2 chemical fixation in the past decades,4ꢀ9 only
very few examples of OTC in the field were reported, and
limited in CO2 reduction to form C1 species (e.g., CH3OH).2
Herein, we report an example of OTC for the transformation
from CO2 to complex fused ring heterocyclic skeleton, 4Hꢀ
quinolizinꢀ4ꢀones. To date, 4Hꢀquinolizinꢀ4ꢀone derivatives
have been explored for their unique physicochemical properꢀ
ties, and serve as several experimental drugs as possible treatꢀ
ments for spinal muscular atrophy, immunoglobulin E related
diseases, Type 2 diabetes, Alzheimer’s disease, HIV10 and
intracellular 3D Mg2+ imaging.11 It is noted that published
syntheses of 4Hꢀquinolizinꢀ4ꢀone, although effective, rely on
harsh reaction conditions, require the use of strong base, or are
based on relatively expensive metal catalysts (Scheme 1a).12 In
this multicomponent oneꢀpot reaction, CO2 is combined with a
terminal alkyne and a 2ꢀsubstituted pyridine precursor, in the
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presence of cost efficient Ag2O (with loading amount as low
as 500 ppm) and Cs2CO3 as coꢀcatalysts. The reaction generꢀ
ates 4Hꢀquinolizinꢀ4ꢀone derivative with overall yields up to
99% and a good substrate scope (27 examples). The OTC
method also benefits from needless small organic molecule as
ligand or catalyst, or additional catalyst carrier. The potential
utility of this procedure is illustrated by the transformation of
the products into diverse derivatives and potential drug.
Page 2 of 8
of the aromatic terminal alkyne species, regardless of bearing
electron withdrawing (3bꢀ3i) or electron donating (3jꢀ3m)
functional groups, 4Hꢀquinolizinꢀ4ꢀones were obtained in
good to excellent yields (48% ꢀ 99%). However, in the case of
the 4ꢀsubstituted aryls bearing nitro or cyano substituents, no
appreciable yield of products was obtained. The reaction was
carried out successfully when 3ꢀethynylthiophene was used as
a test heterocyclic substrate (3n). Good yields were also obꢀ
tained when alkylꢀsubstituted terminal alkynes were used (3p,
3q). It is worth noting that trimethylsilyl protected alkyne,
such as trimethyl(phenylethynyl)silane, could successfully
applied in this transformation to give out 3a with excellent
yield as 95%. Thus, (furanꢀ2ꢀylethynyl)trimethylsilane could
be used directly instead of the unstable 2ꢀethynylfuran to genꢀ
erate 3o with satisfactory yield.
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Our study began with an exploration of the reaction beꢀ
tween ethynylbenzene (1a) and 2ꢀpyridneacetonitrile (2a) unꢀ
der CO2 at atmospheric pressure. The effects of Ag+ contained
catalyst, base and solvent were screened for the optimization
of conditions (cf. ESI). It was found that in the presence of
Cs2CO3, Ag2O proved most effective as a Ag+ contained cataꢀ
lyst and allowed the oneꢀpot preparation of the target 4Hꢀ
quinolizinꢀ4ꢀone derivative, namely 4ꢀoxoꢀ2ꢀphenylꢀ4Hꢀ
quinolizineꢀ1ꢀcarbonitrile (3a), in highest 97% yield when
N,Nꢀdimethylformamide (DMF) was used as the solvent and
the catalyst loading level was 0.5 mole% based on the alkyne.
Product 3a was fully characterized via NMR spectroscopy,
high resolution mass spectrometry (HRMS), and single crystal
Xꢀray diffraction analysis.
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The effect of substitutes on the pyridinyl ring was also exꢀ
plored. Typical functional groups, such as chlorine (3r), broꢀ
mine (3s), methyl (3t) and cyano (3u) were well tolerated givꢀ
ing products in 62% to 92% yield. When the pyridine core was
replaced with quinoline or isoquinoline, the corresponding
products, 3v and 3w, were obtained in excellent yields (95%
and 90%, respectively) under the standard optimized condiꢀ
tions. The cyano group on the 2ꢀmethylpyridinyl moiety could
be replaced by a variety of other electron withdrawing funcꢀ
tional groups (e.g., ‒CO2Et, ‒CO2Me, ‒COPh) as illustrated
by the preparation of targets 3xꢀ3z in good yield (84% ꢀ 92%).
Scheme 2. Substrate Scope a.
Scheme 3. Mechanistic studies.
A number of control experiments and isotopeꢀlabeling studꢀ
ies were carried out in an effort to obtain insights into the
mechanism of the oneꢀpot reaction. Little if any 4Hꢀ
quinolizinꢀ4ꢀone product was obtained when the reaction was
carried out under Ar was instead of CO2. 13Cꢀisotope labelling
experiments revealed that the carbonyl groups in the 4Hꢀ
quinolizinꢀ4ꢀone products comes predominantly from CO2
(Scheme 3a). Again, no target product were observed if the
EtBr was omitted from the reaction. When the pyridine subꢀ
strate was omitted from the reaction, ethyl 3ꢀphenylpropiolate
was isolated cleanly in 94% yield (cf. ESI). Furthermore,
when ethyl 3ꢀphenylpropiolate was prepared independently
and used as the starting material, compound 3a was obtained
in 92% yield (Scheme 3b). These findings provide support for
the conclusion that CO2 serves as the dominant carbon source
for the carbonyl group present in the produces. They also are
consistent with the reasonable supposition that ethyl 3ꢀ
phenylpropiolate serves as a key intermediate that under the
a Reaction conditions: 1 (1.0 mmol), EtBr (2.0 mmol), 2 (2.0
mmol), Ag2O (0.5 mol %), Cs2CO3 (3.0 mmol), DMF (5 mL),
CO2 (1 atm). Yields are those of isolated products. b Trimeꢀ
thyl(phenylethynyl)silane was used as the substrate. (Furanꢀ
2ꢀylethynyl)trimethylsilane was used as the substrate.
c
Following this predicative work, efforts were made to exꢀ
plore the substrate scope and generality of the optimized reacꢀ
tion conditions for the synthesis of 3a (Scheme 2). In the case
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The Journal of Organic Chemistry
conditions of the present tandem reaction undergoes further
tion products were detected when a series of usual Michael
donors were used (cf. ESI). We thus suggest that expansion of
the conjugated system provides a key driving force for the
second step.
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cyclization in the presence of 2ꢀpyridineacetonitrile and relatꢀ
ed substrates to form the target 4Hꢀquinolizinꢀ4ꢀones. Further
study revealed that the second step of the present tandem reacꢀ
tion is base catalyzed. Common bases, such as Cs2CO3, KOH,
NaOH, KOBut, when present at the 20 mol% level could be
used to catalyze the second step providing good to excellent
yields (Scheme 3b). In order to capture the possible intermediꢀ
ate in the second step, a “blocked” pyridine substrate, namely
2ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ1ꢀmethylpyridinꢀ1ꢀium iodide, was
subject to this reaction (Scheme 3c). The isolable diene was
believed to undergo intramolecular Nꢀacylation if the blocked
methyl group was removed. Furthermore, the deuterium isoꢀ
topeꢀlabeling experiment revealed that the proton on 3ꢀsite of
4Hꢀquinlizinꢀ4ꢀone does not come from the methylene group
of the pyridine substrate (cf. ESI).
To illustrate the scalability of this strategy, a gramꢀscale reꢀ
action with a lower Ag2O loading level (500 ppm) was carried
out to give 3a with yields as 75% (Scheme 5a). The functionꢀ
ality and usability of this strategy was further verified by the
transformations of 3y to indeno[2,1ꢀa]quinolizineꢀ6,12ꢀdione
5, 2ꢀphenylꢀ4Hꢀquinolizinꢀ4ꢀone 6, bromide 7 and the potent
spinal muscular atrophy drug 9 (Scheme 5b).
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Scheme 5. Gram-scale synthesis and synthetic application.
Scheme 4. Proposed mechanism.
In summary, we have developed an orthogonal tandem caꢀ
talysis (OTC) system for CO2 chemical fixation to construct
molecular skeleton more complicated than C1 molecular strucꢀ
ture. Specifically, Ag2O and Cs2CO3 coꢀmediated oneꢀpot
tandem reaction for 4Hꢀquinlizinꢀ4ꢀone skeleton construction
from CO2, alkyne, and 2ꢀsubstituted pyridine in the presence
of EtBr. Various 4Hꢀquinlizinꢀ4ꢀones were synthesized in
moderate to excellent yields (48%ꢀ99%) under ambient condiꢀ
tions. The total tandem reaction combines two independent
steps, namely a silverꢀcatalyzed carboxylation (P1) and base
catalyzed cyclization (P2) in one system, and is easy to carry
out on up to the multiꢀgram scale. It also provides an integratꢀ
ed platform for constructing more complex structures, such as
those embodied in the experimental drug 9, using CO2 as a key
precursor.
On the basis of the above results and prior studies involving
the preparation of alkyne carboxylic acids via CO2 capture and
4Hꢀquinolizinꢀ4ꢀones via cyclization of substituted pyridines,
the OTC process containing twoꢀstage reaction pathway
shown in Scheme 4 is proposed. In the first catalytic cycle,
designated as P1, the Ag(I) species activates the terminal alꢀ
EXPERIMENTAL SECTION
−
kyne with cesium carbonate to form the CsCO3 ꢀcoordinated
silver acetylide intermediate.13 CO2 insertion into the Agꢀ
alkyne bond, followed by the ethyl bromideꢀmediated esterifiꢀ
cation, gives the ethyl propynoate intermediate. Analogous to
what has been proposed previously by Watson and coworkꢀ
ers,12d the 2ꢀsubstituded pyridine undergoes deprotonation to
provide an anion that reacts with ethyl propynoate to produce
an alkene intermediate I, which undergoes cis-trans rearꢀ
rangement through a series of protonation and deprotonations
steps in the presence of an appropriate base, such as Cs2CO3
(sequence P2). Our findings offer a deeper insight about the
transformation mechanism from alkene intermediate to 4Hꢀ
quinolizinꢀ4ꢀones. It is suggested that the diene intermediate
(IIA) derives from the olefin intermediate (I), which is folꢀ
lowed by intramolecular Nꢀacylation of the pyridine to give
the annulated product. It is noted that sequence P2 also distinꢀ
guishes from a typical Michael additional route, since no reacꢀ
General Considerations. Unless stated otherwise, all reacꢀ
tions were conducted in Schleck tubes. All chemicals which
are commercially available were used without further purificaꢀ
tion unless otherwise noted. Thin layer chromatography (TLC)
was performed on silica gel plates (60Fꢀ254) using UVꢀlight
(254 and 365 nm). Chromatography was conducted on silica
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gel (200ꢀ300 mesh). H NMR, 13C NMR spectra were recordꢀ
ed on a Bruker Advance 600 or 400 MHz spectrometer at amꢀ
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bient temperature. All H NMR spectra are reported in parts
per million (ppm) downfield of TMS and were measured relaꢀ
tive to the signals for residual CHCl3 (7.26 ppm) or H2O (4.79
ppm). All 13C NMR spectra are reported in ppm relative to
1
residual CHCl3 (77.16 ppm) and were obtained with H deꢀ
coupling. The following abbreviations were used to explain
the multiplicities: s = singlet, d = doublet, t = triplet, q = quarꢀ
tet, m = multiplet. Coupling constants, J, are reported in hertz
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Page 4 of 8
(Hz). Mass spectra were recorded on an AB SCIEX Triple
TOF 5600+ or Bruker Solarix XR FTMS spectrometer.
1H). 13C NMR (151 MHz, CDCl3) δ157.0, 152.3, 146.4, 138.4,
135.3, 135.0, 130.3, 130.2, 129.0, 128.6, 126.7, 123.9, 116.9,
108.6, 100.1, 84.9. HRMS (ESI): Calcd. C16H9ClN2O, [M]+•
280.0403, Found. 280.0403.
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Typical procedure for the synthesis of 3 and 8 from alkynes.
An ovenꢀdried 25 mL Schleck tube was charged with Ag2O
(0.5 mol %), Cs2CO3 (3.0 mmol), and a magnetic stirring bar.
The Schleck tube was then charged and recharged with CO2
for three times. Alkyne 1 (1 mol), EtBr (2.0 mmol) and DMF
(5 mL) was added into the tube and then heated at 50 oC. After
12 h, 2ꢀsubstituted pyridine 2 (2.0 mmol in 2 mL DMF) were
added into the tube and heated at 100 oC for another 4 h. After
cooling, the mixture was filtered and the solvent was then
removed under reduced pressure. The residue was purified by
column chromatography on silica gel (200ꢀ300 mesh, eluent as
the mixture of ethyl acetate and petroleum ether, 1/3, v/v) to
afford the corresponding product.
2-(3-chlorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3d).
1
255 mg, 91 % yield, yellow solid; m.p. 204.0ꢀ204.5 ⁰C; H
NMR (400 MHz, CDCl3) δ 9.28 (d, J = 7.2 Hz, 1H), 8.14 (d, J
= 8.9 Hz, 1H), 7.82 – 7.76 (m, 1H), 7.61 – 7.56 (m, 2H), 7.54
– 7.49 (m, 2H), 7.31 – 7.26 (m, 1H), 6.59 (s, 1H). 13C NMR
(101 MHz, CDCl3) δ 157.1, 152.6, 146.4, 136.5, 135.3, 135.1,
129.9, 129.3, 129.0, 123.9, 117.0, 116.9, 108.5, 84.9. HRMS
(ESI): Calcd. C16H10ClN2O, [M+H]+• 281.0482 Found.
281.0478.
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2-(2-fluorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3e).
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261 mg, 99 % yield, yellow solid; m.p. 199.4ꢀ199.8 ⁰C; H
Typical procedure for the synthesis of 3a and 3o from
TMS-protected alkynes. An ovenꢀdried 25 mL Schleck tube
was charged with Ag2O (0.5 mol %), Cs2CO3 (3.0 mmol), and
a magnetic stirring bar. The Schleck tube was then charged
and recharged with CO2 for three times. TMSꢀprotected alkyne
(1.0 mol) and DMF (5 mL) was added into the tube and then
NMR (600 MHz, CDCl3) δ 9.28 (d, J = 7.2 Hz, 1H), 8.12 (d, J
= 8.9 Hz, 1H), 7.82 – 7.69 (m, 1H), 7.59 – 7.40 (m, 2H), 7.32
– 7.27 (m, 2H), 7.24 (t, J = 8.9 Hz, 1H), 6.61 (s, 1H). 13C
NMR (151 MHz, CDCl3) δ 160.0, 158.4, 157.0, 148.6, 145.9,
135.0, 132.0, 130.6, 128.9, 124.7, 123.8, 116.9, 116.5, 110.0,
86.5. HRMS (ESI): Calcd. C16H10FN2O, [M+H]+• 265.0777,
Found. 265.0773.
o
heated at 50 C. After 12 h, EtBr (2.0 mmol in 1 mL DMF)
was added and stirred for another 4 h. Then, 2ꢀ(pyridinꢀ2ꢀ
2-(3-fluorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3f).
yl)acetonitrile 2a (2.0 mmol in 2 mL DMF) were added into
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248 mg, 94 % yield, yellow solid; m.p. 196.3ꢀ196.5 ⁰C; H
o
the tube and heated at 100 C for 4 h. After cooling, the mixꢀ
NMR (600 MHz, CDCl3) δ9.29 (d, J = 7.2 Hz, 1H), 8.15 (d, J
= 8.9 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.55 – 7.47 (m, 1H),
7.43 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (d, J =
9.3 Hz, 1H), 7.29 (t, J = 6.8 Hz, 1H), 7.22 (td, J = 8.3, 2.0 Hz,
1H), 6.60 (s, 1H). 13C NMR (151 MHz, CDCl3) δ163.6, 162.0,
157.1, 152.5, 146.4, 138.7, 135.3, 130.7, 129.0, 124.4, 123.9,
117.0, 115.8, 115.6, 108.6, 84.9. HRMS (ESI): Calcd.
C16H10FN2O, [M+H]+• 265.0777, Found. 265.0774.
ture was filtered and the solvent was then removed under reꢀ
duced pressure. The residue was purified by column chromaꢀ
tography on silica gel (200ꢀ300 mesh, eluent as the mixture of
ethyl acetate and petroleum ether, 1/3, v/v) to afford the correꢀ
sponding product. 3a, 95 % yield; 3o, 90 % yield.
4-oxo-2-phenyl-4H-quinolizine-1-carbonitrile (3a). 238 mg,
1
97 % yield, yellow solid; m.p. 193.8ꢀ194.4 ⁰C; H NMR (600
MHz, CDCl3) δ 9.28 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.9 Hz,
1H), 7.81 – 7.75 (m, 1H), 7.67 – 7.62 (m, 2H), 7.53 (dd, J =
5.1, 1.9 Hz, 3H), 6.63 (s, 1H). 13C NMR (151 MHz, CDCl3) δ
157.1, 153.8, 146.3, 136.6, 135.0, 130.0, 128.9, 128.4, 123.7,
117.0, 116.7, 108.5 100.0, 85.1. HRMS (ESI): Calcd.
C16H10N2O, [M]+• 246.0793, Found. 246.0797.
4-oxo-2-phenyl-4H-quinolizine-4-13C-1-carbonitrile(3a -13C).
238 mg, 97 % yield, yellow solid; m.p. 189.3ꢀ190.4 ⁰C; 1H
NMR (600 MHz, CDCl3) δ 9.28 (d, J = 7.2 Hz, 1H), 8.15 (d, J
= 8.9 Hz, 1H), 7.66 – 7.61 (m, 2H), 7.53 (dd, J = 5.1, 1.9 Hz,
3H), 7.27 (td, J = 6.9, 1.0 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H).
13C NMR (151 MHz, CDCl3) δ157.1, 153.8, 146.3, 136.7,
135.0, 130.1, 128.9, 128.5, 123.8, 117.1, 116.7, 108.8, 108.3,
85.1. HRMS (ESI): C1513CH11N2O, [M+H]+• Calcd. 248.0905,
Found. 248.0908..
2-(4-fluorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3g).
1
219 mg, 83 % yield, yellow solid; m.p. 202.2ꢀ202.8 ⁰C; H
NMR (600 MHz, CDCl3) δ 9.28 (d, J = 7.2 Hz, 1H), 8.14 (d,
J = 8.9 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.64 (ddd, J = 8.3,
5.3 Hz, 2H), 7.28 (t, J = 6.8 Hz, 2H), 7.22 (t, J = 8.5 Hz, 2H),
6.59 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 164.7, 163.1,
157.0, 152.8, 146.4, 135.2, 132.7, 130.6, 128.9, 123.8, 116.8,
116.2, 108.5, 85.0. HRMS (ESI): Calcd. C16H10FN2O,
[M+H]+• 265.0777, Found. 265.0770.
4-oxo-2-(2-(trifluoromethyl)
phenyl)-4H-quinolizine-1-
carbonitrile (3h). 261 mg, 83 % yield, yellow solid; m.p.
1
241.5ꢀ241.7 ⁰C; H NMR (600 MHz, CDCl3) δ 9.29 (d, J =
7.2 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H),
7.80 (td, J = 7.8, 1.1 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.62 (t,
J = 7.7 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.30 (td, J = 6.1, 1.1
Hz, 1H), 6.53 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 156.5,
152.0, 145.55, 135.3, 135.2, 132.0, 130.3, 129.6, 129.0, 126.7,
126.7, 123.7, 116.9, 116.0, 109.9, 86.8. HRMS (ESI): Calcd.
C17H9F3N2O, [M]+• 314.0667, Found. 314.0667.
2-(2-chlorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3b).
1
274 mg, 98 % yield, yellow solid; m.p. 195.4ꢀ195.8 ⁰C; H
NMR (600 MHz, CDCl3) δ 9.29 (d, J = 7.1 Hz, 1H), 8.09 (d, J
= 8.9 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.54 (d, J = 7.8 Hz,
1H), 7.36 ꢀ7.49 (m, 3H), 7.29 (t, J = 6.8 Hz, 1H), 6.56 (s, 1H).
13C NMR (151 MHz, CDCl3) δ157.0, 151.7, 145.7, 135.7,
135.0, 132.2, 130.8, 130.2, 128.8, 127.1, 123.7, 116.91, 116.1,
109.8, 86.7. HRMS (ESI): Calcd. C16H9ClN2O, [M]+•
280.0403, Found. 280.0400.
4-oxo-2-(4-(trifluoromethyl)phenyl)-4H-quinolizine-1-
carbonitrile (3i). 226 mg, 72 % yield, yellow solid; m.p.
211.3ꢀ211.7 ⁰C; 1H NMR (600 MHz, CDCl3) δ 9.30 (d, J = 7.2
Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.84 – 7.81 (m, 1H), 7.80
(d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.31 (td, J = 7.1,
1.1 Hz, 1H), 6.61 (s, 1H). 13C NMR (151 MHz, CDCl3)
δ157.0, 152.3, 146.4, 140.2, 135.4, 132.2, 132.0, 129.1, 129.0,
126.0, 123.9, 117.1, 116.7, 108.7, 84.8. HRMS (ESI): Calcd.
C17H9F3N2O,, [M]+• 314.0667, Found. 314.0669.
2-(3-chlorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3c).
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213 mg, 76 %, yellow solid; m.p. 219.0ꢀ219.6 ⁰C; H NMR
(600 MHz, CDCl3) δ 9.29 (d, J = 7.1 Hz, 1H), 8.15 (d, J = 8.9
Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 7.3
Hz, 1H), 7.51 – 7.45 (m, 2H), 7.30 (t, J = 6.8 Hz, 1H), 6.59 (s,
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The Journal of Organic Chemistry
CDCl3) δ157.3, 156.5, 145.8, 134.5, 128.7, 123.1, 116.5,
2-(3-methoxyphenyl)-4-oxo-4H-quinolizine-1-carbonitrile
(3j). 270 mg, 98 % yield, yellow solid; m.p. 173.9ꢀ174.4 ⁰C;
1H NMR (600 MHz, CDCl3) δ 9.28 (d, J = 7.2 Hz, 1H), 8.15
(d, J = 8.9 Hz, 1H), 7.78 (dd, J = 11.5, 4.1 Hz, 1H), 7.43 (t, J
= 8.0 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.6 Hz,
1H), 7.16 (s, 1H), 7.05 (dd, J = 8.3, 1.8 Hz, 1H), 6.64 (s, 1H),
3.88 (s, 3H). 13C NMR (151 MHz, CDCl3) δ159.8, 157.2,
153.7, 146.3, 137.9, 135.0, 130.1, 128.9, 123.8, 120.9, 117.0,
116.7, 115.9, 113.9, 108.6, 85.2, 55.5. HRMS (ESI): Calcd.
C17H12N2O2, [M]+• 276.0899, Found 276.0897.
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4
5
6
7
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116.1, 108.3, 86.4, 34.9, 31.7, 22.4, 13.8. HRMS (ESI): Calcd.
C14H15N2O, [M+H]+• 227.1184, Found. 227.1174.
2-cyclopropyl-4-oxo-4H-quinolizine-1-carbonitrile (3q). 202
1
mg, 96 % yield, yellow solid; m.p. 207.9ꢀ208.2 ⁰C; H NMR
(600 MHz, CDCl3) δ 9.16 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 8.9
Hz, 1H), 7.71 (td, J = 5.7, 1.1 Hz, 1H), 7.17 (td, J = 6.1, 1.1
Hz, 1H), 5.99 (s, 1H), 2.29 – 2.23 (m, 1H), 1.29 – 1.22 (m,
2H), 1.00 – 0.91 (m, 2H). 13C NMR (151 MHz, CDCl3)
δ158.4, 157.5, 145.3, 134.7, 128.7, 122.9, 116.7, 116.1, 101.9,
87.1, 14.6, 11.4. HRMS (ESI): Calcd. C13H11N2O, [M+H]+•
211.0871, Found 211.0864.
9
2-(4-methoxyphenyl)-4-oxo-4H-quinolizine-1-carbonitrile
(3k). 132 mg, 48 % yield, yellow solid; m.p. 194.4ꢀ194.9 ⁰C;
1H NMR (600 MHz, CDCl3) δ 9.27 (d, J = 7.2 Hz, 1H), 8.13
(d, J = 8.9 Hz, 1H), 7.76 (td, J = 5.6, 1.0 Hz, 1H), 7.62 (d, J =
8.8 Hz, 2H), 7.24 (dd, J = 7.0, 1.0 Hz, 1H), 7.05 (d, J = 8.8
Hz, 2H), 6.61 (s, 1H), 3.88 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 161.3, 157.3, 153.5, 146.4, 134.9, 130.1, 128.9,
123.8, 117.4, 116.5, 114.5, 108.2, 85.1, 55.5. HRMS (ESI):
Calcd. C17H12N2O2, [M]+• 276.0899, Found 276.0901.
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7-chloro-4-oxo-2-phenyl-4H-quinolizine-1-carbonitrile (3r).
1
174 mg, 62 % yield, yellow solid; m.p. 220.7ꢀ221.1 ⁰C; H
NMR (600 MHz, CDCl3) δ 9.29 (d, J = 1.6 Hz, 1H), 8.09 (d, J
= 9.4 Hz, 1H), 7.70 (dd, J = 9.4, 2.0 Hz, 1H), 7.64 – 7.61 (m,
2H), 7.54 – 7.52 (m, 3H), 6.66 (s, 1H). 13C NMR (151 MHz,
CDCl3) δ156.2, 153.7, 144.5, 136.3, 136.0, 130.3, 129.0,
128.5, 126.7, 125.7, 124.8, 116.6, 109.5, 86.0. HRMS (ESI):
Calcd. C16H10ClN2O, [M+H]+• 281.0482, Found. 281.0485.
4-oxo-2-(p-tolyl)-4H-quinolizine-1-carbonitrile (3l). 250 mg,
1
96 % yield, yellow solid; m.p. 178.6ꢀ78.9 ⁰C; H NMR (600
7-bromo-4-oxo-2-phenyl-4H-quinolizine-1-carbonitrile (3s).
214 mg, 66 % yield, yellow solid; m.p. 231.7ꢀ232.2 ⁰C; H
1
MHz, CDCl3) δ 9.26 (d, J = 7.1 Hz, 1H), 8.13 (d, J = 8.9 Hz,
1H), 7.76 (t, J = 7.9 Hz 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.33 (d,
J = 7.8 Hz, 2H), 7.25 (t, J = 7.6 Hz ,1H), 6.61 (s, 1H), 2.43 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 157.1, 153.7, 146.2,
140.3, 134.9, 133.7, 129.5, 128.7, 128.3, 123.6, 117.2, 116.5,
108.2, 85.0, 21.4. HRMS (ESI): Calcd. C17H12N2O, [M]+•
260.0950, Found 260.0950.
NMR (600 MHz, CDCl3) δ 9.40 (d, J = 1.4 Hz, 1H), 8.02 (d, J
= 9.4 Hz, 1H), 7.79 (dd, J = 9.4, 1.9 Hz, 1H), 7.66 – 7.59 (m,
2H), 7.57 – 7.51 (m, 3H), 6.66 (s, 1H). 13C NMR (151 MHz,
CDCl3) δ156.1, 153.8, 144.6, 138.1, 136.3, 130.3, 129.0,
129.0, 128.5, 124.7, 116.6, 112.3, 109.6, 86.0. HRMS (ESI):
Calcd. C16H10BrN2O, [M+H]+• 324.9977, Found. 324.9968.
2-(4-(tert-butyl) phenyl)-4-oxo-4H-quinolizine-1-carbonitrile
(3m). 279 mg, 92 % yield, yellow solid; m.p. 146.3ꢀ146.7 ⁰C;
1H NMR (600 MHz, CDCl3) δ 9.27 (d, J = 7.2 Hz, 1H), 8.15
(d, J = 8.9 Hz, 1H), 7.76 (td, J = 8.7, 6.7, 1.2 Hz, 1H), 7.60 (d,
J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.25 (td, J = 6.0, 0.8
Hz, 1H), 6.63 (s, 1H), 1.38 (s, 9H). 13C NMR (151 MHz,
CDCl3) δ157.2, 153.7, 153.4, 146.4, 134.8, 133.6, 128.9,
128.3, 125.9, 123.8, 117.3, 116.5, 108.4, 85.1, 34.9, 31.3.
HRMS (ESI): Calcd. C20H19N2O, [M+H]+• 303.1497 Found,
303.1496.
7-methyl-4-oxo-2-phenyl-4H-quinolizine-1-carbonitrile (3t).
239 mg, 92 % yield, yellow solid; m.p. 217.5ꢀ218.1 ⁰C; H
1
NMR (600 MHz, CDCl3) δ 9.11 (s, 1H), 8.08 (d, J = 9.0 Hz,
1H), 7.66 – 7.65 (m, 1H), 7.64 – 7.63 (m, 1H, 7.54 – 7.50 (m,
3H), 6.60 (s, 1H), 2.49 (s, 3H). 13C NMR (151 MHz, CDCl3) δ
157.0, 153.3, 144.9, 137.9, 136.8, 130.0, 128.9, 128.5, 126.5,
123.3, 117.3, 108.3, 100.0, 84.8, 18.6. HRMS (ESI): Calcd.
C17H13N2O, [M+H]+• 261.1028, Found 261.1022.
Ethyl 7-cyano-4-oxo-2-phenyl-4H-quinolizine-1-carboxylate
(3u). 229 mg, 72 % yield, yellow solid; m.p. 203.8ꢀ204.5 ⁰C;
1H NMR (600 MHz, CDCl3) δ 9.87 (d, J = 0.7 Hz, 1H), 8.20
(dd, J = 9.3, 1.6 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.67 – 7.61
(m, 1H), 7.54 (t, J = 3.3 Hz, 1H), 6.67 (s, 1H), 4.49 (q, J = 7.1
Hz, 1H), 1.46 (t, J = 7.1 Hz, 1H). 13C NMR (151 MHz,
CDCl3) δ163.3, 157.0, 154.4, 146.8, 136.2, 133.5, 132.5,
130.4, 129.0, 128.4, 123.7, 120.4, 116.5, 109.8, 86.1, 62.4,
14.4. HRMS (ESI): Calcd. C19H15N2O3, [M+H]+• 319.1083,
Found 319.1085.
4-oxo-2-(thiophen-3-yl)-4H-quinolizine-1-carbonitrile (3n).
1
229 mg, 91 % yield, yellow solid; m.p. 175.4ꢀ175.9 ⁰C; H
NMR (600 MHz, CDCl3) δ 9.26 (d, J = 7.2 Hz, 1H), 8.13 (d, J
= 8.9 Hz, 1H), 7.92 (dd, J = 2.6, 1.3 Hz, 1H), 7.77 (td, J = 7.1,
1.0 Hz, 1H), 7.50 ꢀ 7.48 (m, 2H), 6.69 (s, 1H). 13C NMR (151
MHz, CDCl3) δ157.2, 147.4, 146.5, 136.9, 135.0, 128.9,
127.4, 127.0, 127.0, 123.7, 117.5, 116.6, 107.5, 84.3. HRMS
(ESI): Calcd. C14H8N2OS, [M]+• 252.0357, Found. 252.0358.
4-oxo-2-(thiophen-3-yl)-4H-quinolizine-1-carbonitrile (3o).
212 mg, 90 % yield, yellow solid; m.p. 244.4ꢀ245.0 ⁰C; H
1-oxo-3-phenyl-1H-pyrido [1, 2-a] quinoline-4-carbonitrile
(3v). 281 mg, 95 % yield, yellow solid; m.p. 256.4ꢀ256.8 ⁰C;
1H NMR (600 MHz, CDCl3) δ 9.82 (d, J = 8.9 Hz, 1H), 7.91
(d, J = 9.3 Hz, 1H), 7.82 (d, J = 9.3 Hz, 1H), 7.77 (dd, J = 7.7,
1.2 Hz, 1H), 7.73 (td, J = 7.3, 1.5 Hz, 1H), 7.70 – 7.68 (m,
2H), 7.64 (t, J = 7.4 Hz, 1H), 7.57 (dd, J = 5.0, 1.8 Hz, 3H),
6.77 (s, 1H). 13C NMR (151 MHz, CDCl3) δ162.9, 151.1,
147.5, 135.8, 135.7, 135.3, 130.2, 130.1, 129.0, 128.4, 127.6,
125.6, 122.3, 120.9, 117.3, 115.6, 88.7. HRMS (ESI): Calcd.
C20H12N2O, [M]+• 296.0950, Found. 296.0951.
1
NMR (400 MHz, CDCl3) δ 9.23 (d, J = 7.3 Hz, 1H), 8.11 (d, J
= 9.0 Hz, 1H), 7.79 – 7.71 (m, 1H), 7.66 (d, J = 1.4 Hz, 1H),
7.61 (d, J = 3.6 Hz, 1H), 7.22 (td, J = 6.0, 1.0 Hz, 1H), 7.00 (s,
1H), 6.63 (dd, J = 3.6, 1.7 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 157.3, 148.1, 146.9, 145.4, 140.0, 135.1, 129.0,
123.6, 117.6, 116.4, 114.7, 113.0, 103.3, 80.5. HRMS (ESI):
C14H9N2O2, Calcd. [M+H]+• 237.0664, Found. 237.0657.
2-butyl-4-oxo-4H-quinolizine-1-carbonitrile (3p). 165 mg, 73
% yield, yellow solid; m.p. 72.3ꢀ72.5 ⁰C; 1H NMR (600 MHz,
CDCl3) δ 9.17 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H),
7.69 (td, J = 5.9, 0.9 Hz, 1H), 7.18 (td, J = 6.3, 0.9 Hz, 1H),
6.44 (s, 1H), 2.83 – 2.77 (m, 2H), 1.76 – 1.65 (m, 2H), 1.49 –
1.37 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz,
4-oxo-2-phenyl-4H-pyrido [2,1-a] isoquinoline-1-carbonitrile
(3w). 266 mg, 90 % yield, yellow solid; m.p. 170.7ꢀ171.4 ⁰C;
1H NMR (600 MHz, CDCl3) δ 9.72 (d, J = 8.6 Hz, 1H), 9.04
(d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.80 (d, J = 7.8
Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.64 – 7.60 (m, 2H), 7.56 –
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7.51 (m, 3H), 7.36 (d, J = 7.7 Hz, 1H), 6.73 (s, 1H). 13C NMR
δ167.12, 166.74, 161.84, 158.93, 145.62, 139.91, 134.16,
129.34, 128.47, 128.19, 127.89, 114.04, 111.72, 89.55, 59.21,
58.77, 46.26, 14.60, 13.74. HRMS (ESI): Calcd. C21H24NO4,
[M+H]+• 354.1705, Found. 354.1702.
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(151 MHz, CDCl3) δ 158.0, 155.3, 145.8, 137.1, 133.2, 133.0,
129.9, 128.8, 128.7, 127.5, 125.1, 123.1, 119.8, 116.8, 112.5,
85.4. HRMS (ESI): Calcd. C20H12N2O, [M]+• 296.0950, Found.
296.0948.
Typical procedure for the synthesis of 5. A mixture of 3y
(140 mg, 0.5 mmol) and polyphosphoric acid (PPA, 3.0 g) was
stirred at 100 oC overnight. Then, the mixture was poured into
iceꢀwater. Resulting yellow precipitate was collected by filtraꢀ
tion, washed with water, and then dried by air to give inꢀ
deno[2,1ꢀa]quinolizineꢀ6,12ꢀdione 5 100 mg, 81 % yield. Yelꢀ
Ethyl 4-oxo-2-phenyl-4H-quinolizine-1-carboxylate (3x). 246
1
mg, 84 % yield, yellow solid; 127.9ꢀ128.5 ⁰C; H NMR (600
MHz, CDCl3) δ 9.26 (d, J = 7.3 Hz, 1H), 8.23 (d, J = 9.2 Hz,
1H), 7.56 – 7.54 (m, 1H), 7.44 – 7.40 (m, 3H), 7.40 – 7.37 (m,
2H), 7.13 (td, J = 6.0, 1.2 Hz, 1H), 6.59 (s, 1H), 3.96 (q, J =
7.2 Hz, 2H), 0.79 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 167.4, 157.6, 152.2, 142.3, 140.3, 132.4, 128.5,
128.4, 128.0, 127.5, 123.3, 115.6, 109.1, 106.9, 61.32, 13.4.
HRMS (ESI): Calcd. C18H15NO3, [M]+• 293.1052, Found.
293.1055.
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1
low solid; m.p. 251.8ꢀ252.4 ⁰C; H NMR (400 MHz, CDCl3)
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δ9.03 (d, J = 7.3 Hz, 1H), 8.86 (d, J = 8.9 Hz, 1H), 7.74 (d, J =
7.2 Hz, 1H), 7.71 – 7.61 (m, 3H), 7.55 (tt, J = 7.1, 3.4 Hz,
1H), 7.52 – 7.45 (m, 1H), 7.09 – 7.02 (m, 1H), 6.77 (s, 1H).
13C NMR (101 MHz, CDCl3) δ 188.83, 159.58, 153.04,
142.86, 140.18, 138.29, 135.33, 133.48, 131.66, 128.64,
123.48, 122.62, 121.96, 115.88, 105.38, 100.39. HRMS
(ESI): Calcd. C16H10NO2, [M+H]+• 248.0712 Found. 248.0714.
Methyl 4-oxo-2-phenyl-4H-quinolizine-1-carboxylate (3y).
1
243 mg, 87 % yield, yellow solid; m.p. 119.5ꢀ120.2 ⁰C; H
NMR (400 MHz, CDCl3) δ 9.26 (d, J = 7.2 Hz, 1H), 8.19 (d, J
= 9.2 Hz, 1H), 7.59 – 7.51 (m, 1H), 7.42 (tt, J = 7.7, 5.9 Hz,
5H), 7.13 (dd, J = 10.0, 3.8 Hz, 1H), 6.60 (s, 1H), 3.48 (s, 3H).
13C NMR (101 MHz, CDCl3) δ167.96, 157.60, 152.03, 142.30,
140.12, 132.43, 128.56, 128.06, 127.45, 123.36, 115.64,
109.16, 106.70, 52.05. HRMS (ESI): Calcd. C17H13NO3, [M]+•
279.0895, Found. 279.0894.
Typical procedure for the synthesis of 6. A mixture of 3y
(140 mg, 0.5 mmol), KOH (56 mg, 1.0 mmol), EtOH (2 mL)
and H2O (1.5 mL) was stirred under reflux overnight. After
cooling, the reaction mixture was acidized by diluted HCl to
pH = 1. The yellow precipitate was collected by filtration and
purified by column chromatography on silica gel (200ꢀ300
mesh, eluent as the mixture of ethyl acetate and petroleum
ether, 1/3, v/v) to afford the 2ꢀphenylꢀ4Hꢀquinolizinꢀ4ꢀone 6
1-benzoyl-2-phenyl-4H-quinolizin-4-one (3z). 299 mg, 92 %
yield, yellow solid; m.p. 144.4ꢀ144.8 ⁰C; 1H NMR (400 MHz,
CDCl3) δ 9.15 (d, J = 7.1 Hz, 1H), 7.85 (d, J = 7.2 Hz, 2H),
7.57 (d, J = 8.8 Hz, 1H), 7.52 – 7.43 (m, 2H), 7.41 – 7.32 (m,
4H), 7.29 – 7.26 (m, 3H), 7.11 – 7.06 (m, 1H), 6.76 (s, 1H)..
13C NMR (101 MHz, CDCl3) δ195.83, 156.32, 150.72, 142.55,
138.35, 138.13, 132.97, 131.46, 129.41, 128.72, 128.53,
128.47, 128.45, 127.74, 125.61, 117.82, 115.81, 104.63..
HRMS (ESI): Calcd. C22H15NO2, [M]+• 325.1103, Found.
325.1107.
1
96 mg, 86 %yield. Yellow solid; m.p. 126.7ꢀ127.2 ⁰C; H
NMR (400 MHz, CDCl3) δ 9.11 (d, J = 7.3 Hz, 1H), 7.70 (dd,
J = 8.0, 1.4 Hz, 2H), 7.55 – 7.41 (m, 4H), 7.35 (td, J = 5.7, 0.9
Hz, 1H), 7.00 (td, J = 6.3, 1.3 Hz, 1H), 6.89 (s, 1H), 6.88 (s,
1H). 13C NMR (101 MHz, CDCl3) δ158.8, 150.5, 142.4, 138.6,
129.8, 129.4, 129.1, 127.3, 125.8, 114.9, 106.7, 102.2. HRMS
(ESI): Calcd. C15H12NO, [M+H]+• 222.0919 Found. 222.0915.
Typical procedure for the synthesis of 7. A mixture of 3y
(140 mg, 0.5 mmol), NBS (178 mg, 1.0 mmol), CCl4 (10 mL)
was stirred under at room temperature overnight. Then, the
solvent was removed and the residue was purified by column
chromatography on silica gel (200ꢀ300 mesh, ethyl aceꢀ
tate/petroleum ether = 1/5, v/v) to afford the methyl 3ꢀbromoꢀ
4ꢀoxoꢀ2ꢀphenylꢀ4Hꢀquinolizineꢀ1ꢀcarboxylate 7 150 mg, 86
%yield. Green solid; m.p. 182.7ꢀ183.2 ⁰C; 1H NMR (400
MHz, CDCl3) δ 9.30 (d, J = 7.3 Hz, 1H), 8.00 (d, J = 9.1 Hz,
1H), 7.60 – 7.54 (m, 1H), 7.49 – 7.38 (m, 3H), 7.31 – 7.24 (m,
3H), 7.18 (t, J = 6.7 Hz, 1H), 3.38 (s, 3H).. 13C NMR (101
MHz, CDCl3) δ 166.90, 154.85, 150.74, 140.04, 139.33,
132.24, 128.50, 128.45, 128.21, 128.12, 127.99, 123.41,
116.54, 108.98, 106.02, 52.22. HRMS (ESI): Calcd.
C17H13BrNO3, [M+H]+• 358.0079 Found. 358.0073.
2-(3,4-dimethoxyphenyl)-7-fluoro-4-oxo-4H-quinolizine-1-
carbonitrile (8). 146 mg, 45 % yield, yellow solid; m.p.
222.7ꢀ223.2 ⁰C; 1H NMR (400 MHz, CDCl3) δ 9.38 (d, J = 1.4
Hz, 1H), 8.00 (d, J = 9.4 Hz, 1H), 7.77 (dd, J = 9.4, 1.8 Hz,
1H), 7.26 (m, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.4
Hz, 1H), 6.67 (s, 1H), 3.96 (s, 3H), 3.96 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 156.1, 153.4, 150.9, 149.2, 144.7, 138.0,
129.0, 128.6, 124.7, 121.6, 117.0, 112.1, 111.6, 111.3, 109.0,
85.8, 56.2, 56.1. HRMS (ESI): Calcd. C18H14FN2O3, [M+H]+•
325.0988, Found. 325.0980.
Typical procedure for the synthesis of 4. An ovenꢀdried 25
mL Schleck tube was charged with 2ꢀ(2ꢀethoxyꢀ2ꢀoxoethyl)ꢀ1ꢀ
methylpyridinꢀ1ꢀium iodide (154 mg, 0.5 mol), Cs2CO3 (326
mg, 1.0 mmol), and a magnetic stirring bar. The Schleck tube
was then charged and recharged with Ar for three times. Ethyl
3ꢀphenylpropiolate (174 mg 1.0 mol in 1mL DMF) and DMF
ASSOCIATED CONTENT
Supporting Information
o
(4 mL) was added into the tube and then heated at 100 C
overnight. After cooling, the mixture was filtered and the solꢀ
vent was then removed under reduced pressure. The residue
was purified by column chromatography on silica gel (200ꢀ
300 mesh, ethyl acetate/petroleum ether = 1/3, v/v) to afford
the diethyl (2Z,4Z)ꢀ4ꢀ(1ꢀmethylpyridinꢀ2(1H)ꢀylidene)ꢀ3ꢀ
phenylpentꢀ2ꢀenedioate (4) 134 mg, 76 % yield. Red solid;
The Supporting Information is available free of charge on the
ACS Publications website.
Optimization information and NMR spectra of all new comꢀ
pounds (PDF).
Crystallographic information for 3a (CIF), 3p (CIF), 3q (CIF), 3v
(CIF), 3w (CIF), 3x (CIF), 3z (CIF), 4 (CIF) and 5 (CIF).
1
m.p. 140.0ꢀ140.4 ⁰C; H NMR (400 MHz, CDCl3) δ7.63 –
AUTHOR INFORMATION
7.47 (m, 1H), 7.36 – 7.30 (m, 1H), 7.19 – 7.13 (m, 1H), 6.55
(td, J = 6.7, 1.3 Hz, 1H), 5.65 (s, 1H), 3.95 (q, J = 7.1 Hz, 1H),
3.78 (s, 1H), 3.71 (q, J = 7.1 Hz, 1H), 1.13 (t, J = 7.1 Hz, 1H),
0.56 (t, J = 7.1 Hz, 1H).. 13C NMR (101 MHz, CDCl3)
Corresponding Author
†hanyuangong@bnu.edu.cn
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The Journal of Organic Chemistry
Chem. Int. Ed. 2016, 55, 7296–7343. (b) Li, Y.; Cui, X.; Dong, K.;
‡20050062@ruc.edu.cn
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Catalytic Methylation Reactions. ACS Catal. 2017, 7, 1077–1086.
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Nolan, S. P. Carboxylation of NꢀH/CꢀH Bonds Using NꢀHeterocyclic
Carbene Copper(I) Complexes. Angew. Chem. Int. Ed. 2010, 49,
8674–8677. (b) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Copperꢀ
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G. R.; Yoshino, T.; Kanan, M. W. Carbon dioxide utilization via
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1
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ORCID
HanꢀYuan Gong: 0000ꢀ0003ꢀ4168ꢀ7657
LiꢀJin Xu: 0000ꢀ0003ꢀ4067ꢀ8898
Notes
There are no conflicts to declare.
9
ACKNOWLEDGMENT
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H.ꢀY. G. is grateful to the National Natural Science Foundation of
China (21472014 and 21672025), National Basic Research Proꢀ
gram of China (973 Program 2015CB856502), the Young Oneꢀ
ThousandꢀTalents Scheme, the Fundamental Research Funds for
the Central Universities, the Beijing Municipal Commission of
Education, and Beijing National Laboratory for Molecular Sciꢀ
ence (BNLMS) for financial support. L.ꢀJ. X. Thanks the National
Natural Science Foundation of China (21372258) for the support.
We would also like to express our gratitude to Dr. TongꢀLing
Liang and Dr. Xiang Hao for the singleꢀcrystal Xꢀray analyses.
We appreciate Prof. Jonathan L. Sessler for insightful discussion.
(8) Arshadi, S.; Vessally, E.; Sobati, M.; Hosseinian, A.;
Bekhradnia, A. Chemical fixation of CO2 to Nꢀpropargylamines: A
straightforward route to 2ꢀoxazolidinones. J. CO2 Util. 2017, 19, 120–
129.
(9) Sekine, K.; Yamada, T. Silverꢀcatalyzed carboxylation. Chem.
Soc. Rev. 2016, 45, 4524–4532.
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