Note Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
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From CO2 to 4H‑Quinolizin-4-ones: A One-Pot Multicomponent Approach via Ag2O/Cs2CO3 Orthogonal Tandem Catalysis Chao-Chen Dong,†,‡ Jun-Feng Xiang,∥,§ Li-Jin Xu,*,‡ and Han-Yuan Gong*,† †
College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China Department of Chemistry, Renmin University of China, Beijing 100872, P. R. China ∥ Beijing National Laboratory for Molecular Sciences (BNLMS), Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China § University of Chinese Academy of Sciences, Beijing 100049, P. R. China Downloaded via NAGOYA UNIV on June 23, 2018 at 08:22:00 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
‡
S Supporting Information *
ABSTRACT: 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.
O
Scheme 1. Synthetic Methods to 4H-Quinolizin-4-ones
rthogonal tandem catalysis (OTC) is one of the most attractive strategies for complex molecular construction. This methodology simultaneously uses multiple catalysts in a one-pot reaction to produce a final product through sequential mechanistically distinct reaction steps.1 Surprisingly, the examples 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,4−9 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 skeletons, 4H-quinolizin-4-ones. To date, 4H-quinolizin-4-one derivatives have been explored for their unique physicochemical properties and serve as several experimental drugs as possible treatments for spinal muscular atrophy, immunoglobulin E related diseases, Type 2 diabetes, Alzheimer’s disease, HIV,10 and intracellular 3D Mg2+ imaging.11 It is noted that published syntheses of 4H-quinolizin-4-one, 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 one-pot reaction, CO2 is combined with a terminal alkyne and a 2-substituted pyridine precursor in the presence of cost-efficient Ag2O (with loading amount as low as 500 ppm) and Cs2CO3 as co© XXXX American Chemical Society
catalysts. The reaction generates 4H-quinolizin-4-one 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. Our study began with an exploration of the reaction between ethynylbenzene (1a) and 2-pyridneacetonitrile (2a) under CO2 at atmospheric pressure. The effects of Ag+-containing Received: May 24, 2018 Published: June 6, 2018 A
DOI: 10.1021/acs.joc.8b01206 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
trimethylsilyl-protected alkyne, such as trimethyl(phenylethynyl)silane, could be successfully applied in this transformation to give 3a with excellent 95% yield. Thus, (furan-2-ylethynyl)trimethylsilane could be used directly instead of the unstable 2-ethynylfuran to generate 3o with satisfactory yield. The effect of substituents on the pyridinyl ring was also explored. Typical functional groups, such as chlorine (3r), bromine (3s), methyl (3t), and cyano (3u), were well tolerated, giving products in 62−92% 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 conditions. The cyano group on the 2-methylpyridinyl moiety could be replaced by a variety of other electronwithdrawing functional groups (e.g., −CO2Et, −CO2Me, −COPh) as illustrated by the preparation of targets 3x−z in good yield (84−92%). A number of control experiments and isotope-labeling studies were carried out in an effort to obtain insight into the mechanism of the one-pot reaction. Little if any 4Hquinolizin-4-one product was obtained when the reaction was carried out under Ar instead of CO2. 13C-isotope labeling experiments revealed that the carbonyl groups in the 4Hquinolizin-4-one products come predominantly from CO2 (Scheme 3a). Again, no target products were observed if the
catalyst, base, and solvent were screened for the optimization of conditions (Supporting Information). It was found that in the presence of Cs2CO3, Ag2O proved most effective as a Ag+containing catalyst and allowed the one-pot preparation of the target 4H-quinolizin-4-one derivative, namely 4-oxo-2-phenyl4H-quinolizine-1-carbonitrile (3a), in highest 97% yield when N,N-dimethylformamide (DMF) was used as the solvent and the catalyst loading level was 0.5 mol % based on the alkyne. Product 3a was fully characterized via NMR spectroscopy, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction analysis. Following this predictive work, efforts were made to explore the substrate scope and generality of the optimized reaction conditions for the synthesis of 3a (Scheme 2). In the case of Scheme 2. Substrate Scopea
Scheme 3. Mechanistic Studies
EtBr was omitted from the reaction. When the pyridine substrate was omitted from the reaction, ethyl 3-phenylpropiolate was isolated cleanly in 94% yield (Supporting Information). Furthermore, when ethyl 3-phenylpropiolate was prepared independently and used as the starting material, compound 3a was obtained in 92% yield (Scheme 3b). These findings provide support the conclusion that CO2 serves as the dominant carbon source for the carbonyl group present in the products. They also are consistent with the reasonable supposition that ethyl 3-phenylpropiolate serves as a key intermediate that under the conditions of the present tandem reaction undergoes further cyclization in the presence of 2pyridineacetonitrile and related substrates to form the target 4H-quinolizin-4-ones. Further study revealed that the second step of the present tandem reaction is base catalyzed. Common bases, such as Cs2CO3, KOH, NaOH, and KOBut, when present at the 20 mol % level, could be used to catalyze the second step, providing good to excellent yields (Scheme 3b).
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. bTrimethyl(phenylethynyl)silane was used as the substrate. c(Furan-2-ylethynyl)trimethylsilane was used as the substrate.
the aromatic terminal alkyne species, regardless of whether they bear electron-withdrawing (3b−i) or electron-donating (3j−m) functional groups, 4H-quinolizin-4-ones were obtained in good to excellent yields (48−99%). However, in the case of the 4-substituted aryls bearing nitro or cyano substituents, no appreciable yield of products was obtained. The reaction was carried out successfully when 3-ethynylthiophene was used as a test heterocyclic substrate (3n). Good yields were also obtained when alkyl-substituted terminal alkynes were used (3p, 3q). It is worth noting that B
DOI: 10.1021/acs.joc.8b01206 J. Org. Chem. XXXX, XXX, XXX−XXX
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To illustrate the scalability of this strategy, a gram-scale reaction with a lower Ag2O loading level (500 ppm) was carried out to give 3a with yields as high as 75% (Scheme 5a).
To capture the possible intermediate in the second step, a “blocked” pyridine substrate, namely 2-(2-ethoxy-2-oxoethyl)1-methylpyridin-1-ium iodide, was subjected to this reaction (Scheme 3c). The isolable diene was believed to undergo intramolecular N-acylation if the blocked methyl group was removed. Furthermore, the deuterium isotope-labeling experiment revealed that the proton on the 3-site of 4H-quinlizin-4one does not come from the methylene group of the pyridine substrate (Supporting Information). On the basis of the above results and prior studies involving the preparation of alkyne carboxylic acids via CO2 capture and 4H-quinolizin-4-ones via cyclization of substituted pyridines, the OTC process containing the two-stage reaction pathway shown in Scheme 4 is proposed. In the first catalytic cycle,
Scheme 5. Gram-Scale Synthesis and Synthetic Application
Scheme 4. Proposed Mechanism
The functionality and usability of this strategy was further verified by the transformations of 3y to indeno[2,1-a]quinolizine-6,12-dione 5, 2-phenyl-4H-quinolizin-4-one 6, bromide 7, and the potent spinal muscular atrophy drug 9 (Scheme 5b). In summary, we have developed an OTC system for CO2 chemical fixation to construct molecular skeletons more complicated than the C1 molecular structure. Specifically, Ag2O and Cs2CO3 co-mediated one-pot tandem reaction for 4H-quinlizin-4-one skeleton construction from CO2, alkyne, and 2-substituted pyridine in the presence of EtBr. Various 4Hquinlizin-4-ones were synthesized in moderate to excellent yields (48%−99%) under ambient conditions. The total tandem reaction combines two independent steps, namely a silver-catalyzed carboxylation (P1) and base-catalyzed cyclization (P2), in one system and is easy to carry out on up to a multigram scale. It also provides an integrated platform for constructing more complex structures, such as those embodied in the experimental drug 9, using CO2 as a key precursor.
designated as P1, the Ag(I) species activates the terminal alkyne with cesium carbonate to form the CsCO3 −coordinated silver acetylide intermediate.13 CO2 insertion into the Ag−alkyne bond, followed by the ethyl bromidemediated esterification, gives the ethyl propynoate intermediate. Analogous to what has been proposed previously by Watson and co-workers,12d the 2-substituted pyridine undergoes deprotonation to provide an anion that reacts with ethyl propynoate to produce an alkene intermediate I, which undergoes cis−trans rearrangement 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 4H-quinolizin-4-ones. It is suggested that the diene intermediate (IIA) derives from the olefin intermediate (I), which is followed by intramolecular Nacylation of the pyridine to give the annulated product. It is noted that sequence P2 is different from a typical Michael additional route, since no reaction products were detected when a series of the usual Michael donors were used (Supporting Information). We thus suggest that expansion of the conjugated system provides a key driving force for the second step.
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EXPERIMENTAL SECTION
General Considerations. Unless stated otherwise, all reactions were conducted in Schlenk tubes. All chemicals which are commercially available were used without further purification unless otherwise noted. Thin-layer chromatography (TLC) was performed on silica gel plates (60F-254) using UV light (254 and 365 nm). Chromatography was conducted on silica gel (200−300 mesh). 1H and 13C NMR spectra were recorded on a Bruker Advance 600 or 400 MHz spectrometer at ambient temperature. All 1H NMR spectra are reported in parts per million (ppm) downfield of TMS and were measured relative to the signals for residual CHCl3 (7.26 ppm) or H2O (4.79 ppm). All 13C NMR spectra are reported in ppm relative to residual CHCl3 (77.16 ppm) and were obtained with 1H decoupling. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Coupling constants, J, are reported in hertz (Hz). Mass spectra were recorded on an AB SCIEX Triple TOF 5600+ or Bruker Solarix XR FTMS spectrometer. Typical Procedure for the Synthesis of 3 and 8 from Alkynes. An oven-dried 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 three times. C
DOI: 10.1021/acs.joc.8b01206 J. Org. Chem. XXXX, XXX, XXX−XXX
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2-(3-Fluorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3f): 248 mg, 94% yield, yellow solid; mp 196.3−196.5 °C; 1H 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. 2-(4-Fluorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3g): 219 mg, 83% yield, yellow solid; mp 202.2−202.8 °C; 1H 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; mp 241.5−241.7 °C; 1H 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. 4-Oxo-2-(4-(trifluoromethyl)phenyl)-4H-quinolizine-1-carbonitrile (3i): 226 mg, 72% yield, yellow solid; mp 211.3-211.7 °C; 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-Methoxyphenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3j): 270 mg, 98% yield, yellow solid; mp 173.9−174.4 °C; 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. 2-(4-Methoxyphenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3k): 132 mg, 48% yield, yellow solid; mp 194.4−194.9 °C; 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. 4-Oxo-2-(p-tolyl)-4H-quinolizine-1-carbonitrile (3l): 250 mg, 96% yield, yellow solid; mp 178.6−78.9 °C; 1H NMR (600 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. 2-(4-tert-Butylphenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3m): 279 mg, 92% yield, yellow solid; mp 146.3−146.7 °C; 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. 4-Oxo-2-(thiophene-3-yl)-4H-quinolizine-1-carbonitrile (3n): 229 mg, 91% yield, yellow solid; mp 175.4−175.9 °C; 1H NMR (600
Alkyne 1 (1 mol), EtBr (2.0 mmol), and DMF (5 mL) were added into the tube and then heated at 50 °C. After 12 h, 2-substituted pyridine 2 (2.0 mmol in 2 mL of DMF) was added into the tube and heated at 100 °C 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 (200−300 mesh, eluent as the mixture of ethyl acetate and petroleum ether, 1/3, v/v) to afford the corresponding product. Typical Procedure for the Synthesis of 3a and 3o from TMSprotected alkynes. An oven-dried 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 three times. TMS-protected alkyne (1.0 mol) and DMF (5 mL) were added into the tube and then heated at 50 °C. After 12 h, EtBr (2.0 mmol in 1 mL of DMF) was added and the mixture stirred for another 4 h. Then 2-(pyridin-2-yl)acetonitrile 2a (2.0 mmol in 2 mL DMF) was added into the tube and heated at 100 °C for 4 h. After being cooled, the mixture was filtered, and the solvent was then removed under reduced pressure. The residue was purified by column chromatography on silica gel (200−300 mesh, eluent as the mixture of ethyl acetate and petroleum ether, 1/3, v/v) to afford the corresponding product. 3a, 95% yield; 3o, 90% yield. 4-Oxo-2-phenyl-4H-quinolizine-1-carbonitrile (3a): 238 mg, 97% yield, yellow solid; mp 193.8−194.4 °C; 1H 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; mp 189.3−190.4 °C; 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-(2-Chlorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3b): 274 mg, 98% yield, yellow solid; mp 195.4−195.8 °C; 1H 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. 2-(3-Chlorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3c): 213 mg, 76%, yellow solid; mp 219.0−219.6 °C; 1H 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, 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. 2-(3-Chlorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3d): 255 mg, 91% yield, yellow solid; mp 204.0−204.5 °C; 1H 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. 2-(2-Fluorophenyl)-4-oxo-4H-quinolizine-1-carbonitrile (3e): 261 mg, 99% yield, yellow solid; mp 199.4−199.8 °C; 1H 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. D
DOI: 10.1021/acs.joc.8b01206 J. Org. Chem. XXXX, XXX, XXX−XXX
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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. 4-Oxo-2-phenyl-4H-pyrido [2,1-a]isoquinoline-1-carbonitrile (3w): 266 mg, 90% yield, yellow solid; mp 170.7−171.4 °C; 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), 7.56−7.51 (m, 3H), 7.36 (d, J = 7.7 Hz, 1H), 6.73 (s, 1H). 13C NMR (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. Ethyl 4-oxo-2-phenyl-4H-quinolizine-1-carboxylate (3x): 246 mg, 84% yield, yellow solid; 127.9−128.5 °C; 1H 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. Methyl 4-oxo-2-phenyl-4H-quinolizine-1-carboxylate (3y): 243 mg, 87% yield, yellow solid; mp 119.5−120.2 °C; 1H 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. 1-Benzoyl-2-phenyl-4H-quinolizin-4-one (3z): 299 mg, 92% yield, yellow solid; mp 144.4−144.8 °C; 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. 2-(3,4-Dimethoxyphenyl)-7-fluoro-4-oxo-4H-quinolizine-1-carbonitrile (8:). 146 mg, 45% yield, yellow solid; mp 222.7−223.2 °C; 1 H 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 oven-dried 25 mL Schlenk tube was charged with 2-(2-ethoxy-2-oxoethyl)-1methylpyridin-1-ium iodide (154 mg, 0.5 mol), Cs2CO3 (326 mg, 1.0 mmol), and a magnetic stirring bar. The Schlenk tube was then charged and recharged with Ar three times. Ethyl 3-phenylpropiolate (174 mg 1.0 mol in 1 mL DMF) and DMF (4 mL) were added into the tube and then heated at 100 °C overnight. 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 (200−300 mesh, ethyl acetate/petroleum ether = 1/3, v/v) to afford the diethyl (2Z,4Z)-4-(1-methylpyridin-2(1H)-ylidene)-3phenylpent-2-enedioate (4) 134 mg, 76% yield: red solid; mp 140.0− 140.4 °C; 1H NMR (400 MHz, CDCl3) δ7.63−7.47 (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) 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. 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 °C overnight. Then the mixture was poured into ice−water. The
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-(thiophene-3-yl)-4H-quinolizine-1-carbonitrile (3o): 212 mg, 90% yield, yellow solid; mp 244.4−245.0 °C; 1H 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) calcd C14H9N2O2, [M + H]+• 237.0664, found 237.0657. 2-Butyl-4-oxo-4H-quinolizine-1-carbonitrile (3p): 165 mg, 73% yield, yellow solid; mp 72.3−72.5 °C; 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, CDCl3) δ157.3, 156.5, 145.8, 134.5, 128.7, 123.1, 116.5, 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 mg, 96% yield, yellow solid; mp 207.9−208.2 °C; 1H 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. 7-Chloro-4-oxo-2-phenyl-4H-quinolizine-1-carbonitrile (3r): 174 mg, 62% yield, yellow solid; mp 220.7−221.1 °C; 1H 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. 7-Bromo-4-oxo-2-phenyl-4H-quinolizine-1-carbonitrile (3s): 214 mg, 66% yield, yellow solid; mp 231.7−232.2 °C; 1H 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. 7-Methyl-4-oxo-2-phenyl-4H-quinolizine-1-carbonitrile (3t): 239 mg, 92% yield, yellow solid; mp 217.5−218.1 °C; 1H 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; mp 203.8−204.5 °C; 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. 1-Oxo-3-phenyl-1H-pyrido[1, 2-a]quinoline-4-carbonitrile (3v): 281 mg, 95% yield, yellow solid; mp 256.4−256.8 °C; 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) E
DOI: 10.1021/acs.joc.8b01206 J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry resulting yellow precipitate was collected by filtration, washed with water, and then dried in air to give indeno[2,1-a]quinolizine-6,12dione 5 100 mg, 81% yield: yellow solid; mp 251.8−252.4 °C; 1H NMR (400 MHz, CDCl3) 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. 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 being cooled, 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 (200−300 mesh, eluent as the mixture of ethyl acetate and petroleum ether, 1/3, v/v) to afford the 2-phenyl4H-quinolizin-4-one 6 96 mg, 86% yield: yellow solid; mp 126.7− 127.2 °C; 1H 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); 13 C 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 (200−300 mesh, ethyl acetate/petroleum ether = 1/5, v/v) to afford the methyl 3-bromo-4-oxo-2-phenyl-4H-quinolizine-1-carboxylate 7 150 mg, 86% yield: green solid; mp 182.7−183.2 °C; 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.
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ACKNOWLEDGMENTS
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REFERENCES
H.-Y.G. is grateful to the National Natural Science Foundation of China (21472014 and 21672025), National Basic Research Program of China (973 Program 2015CB856502), the Young One-Thousand-Talents Scheme, the Fundamental Research Funds for the Central Universities, the Beijing Municipal Commission of Education, and the Beijing National Laboratory for Molecular Science (BNLMS) for financial support. L.-J.X. thanks the National Natural Science Foundation of China (21372258) for support. We also express our gratitude to Dr. Tong-Ling Liang and Dr. Xiang Hao for the singlecrystal X-ray analyses. We appreciate Prof. Jonathan L. Sessler for insightful discussion.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01206.
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Note
Optimization information and NMR spectra of all new compounds (PDF) Crystallographic data for compound 3a (CIF) Crystallographic data for compound 3p (CIF) Crystallographic data for compound 3q (CIF) Crystallographic data for compound 3v (CIF) Crystallographic data for compound 3w (CIF) Crystallographic data for compound 3x (CIF) Crystallographic data for compound 3z (CIF) Crystallographic data for compound 4 (CIF) Crystallographic data for compound 5 (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] *E-mail:
[email protected]. ORCID
Li-Jin Xu: 0000-0003-4067-8898 Han-Yuan Gong: 0000-0003-4168-7657 Notes
The authors declare no competing financial interest. F
DOI: 10.1021/acs.joc.8b01206 J. Org. Chem. XXXX, XXX, XXX−XXX
Note
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DOI: 10.1021/acs.joc.8b01206 J. Org. Chem. XXXX, XXX, XXX−XXX
